Transition metal-catalyzed processes for the preparation of n-allyl compounds and use thereof

ABSTRACT

The present disclosure provides processes for the N-dealkylation of tertiary amines and the use of transition metal catalysts to prepare tertiary N-allyl amine derivatives and secondary amine derivatives thereof. The tertiary amines can be alkaloids and, more particularly, the tertiary amines can be opioids. In specific embodiments, the present disclosure provides methods for use in processes for the synthesis of naloxone and naltrexone from oripavine.

1. FIELD

The present disclosure provides processes for preparing N-allyl aminesfrom tertiary N-alkyl amines. The disclosed processes includehaloformate-promoted N-dealkylation of a tertiary amine and a subsequenttransition metal-catalyzed allylic decarboxylation to provide theN-allyl amine. The tertiary amines can be alkaloids, and moreparticularly, the tertiary amines can be opioids.

2. BACKGROUND

N-dealkylation of tertiary amines is a key chemical transformation inmany processes for the preparation of clinically and commerciallyimportant compounds. Methods for N-dealkylation of tertiary amines areknown in the art and include reaction of the tertiary amine withcyanogen bromide (see, e.g., U.S. Pat. Nos. 3,254,088 and 3,433,791; andCooley et al., “Amine Dealkylations with Acyl Chlorides” (1989)Synthesis 1-7), dialkyl azodicarboxylates includingdiethylazodicarboxylate and di-iso-propylazodicarboxylate, (see, e.g.,GB 1,124,441), and haloformate reagents, including vinyl, methyl, ethyl,allyl, propyl, heptyl, phenyl, benzyl, α-chloro-ethyl, and2,2,2-tri-chloro-ethyl chloroformates (see, e.g., U.S. Pat. Nos.3,905,981 and 4,472,253; Olofson et al. (1984) J. Org. Chem.49(11):2081-2083; and Rice et al. (1975) J. Org. Chem.40(12):1850-1851).

Additional methods for N-dealkylation, particularly N-demethylation oftertiary amines, involve photochemical cleavage, as well as theformation and hydrolysis of dithiocarbamate, methyoxymethylether, andamine N-oxide intermediates to provide the corresponding secondary aminederivatives (see, e.g., Santamaria et al. (1989) Tetrahedron Lett.30:2927; Santamaria et al. (1990) Tetrahedron Lett. 31:4735; Acosta etal. (1994) J. Chem. Soc., Chem. Commun. 17(7):1985-1986; Murahashi etal. (1988) J. Am. Chem. Soc. 110:8256; Murahashi (1995) Angew. Chem.,Int. Ed., Engl. 34:2443; Polniaszek et al. (1992) J. Org. Chem. 57:4103;Murahashi et al. (1992) Tetrahedron Lett. 33:6991; Murahashi et al.(2003) J. Am. Chem. Soc. 125:15312; McCamley et al. (2003) J. Org. Chem.Soc. 68:9847; Gesson et al., “Preparation of N-Demethyl and N-AlkylAnalogs of L-Rhodosamine” (November 1990) Synlett. 669-670; Rosenau etal. (2004) Org. Lett. 6:541; Menchaca et al. (2003) J. Org. Chem.68:8859; Periasamy et al. (2000) J. Org. Chem. 65:3548; Saaby et al.(2000) Angew. Chem., Int. Ed., Engl. 39(22):4114-4116; Denis et al.(2002) Tetrahedron Lett. 43:4171; and Zhang et al. (2005) Org. Lett.7:3239).

In particular, methods for the preparation of noroxymorphone andnoroxycodone involve removal of the naturally occurring opioid N-methylgroup to provide the corresponding secondary amine. Methods for thepreparation of other semi-synthetic opiate derivatives, e.g., naloxone,naltrexone, nalorphine, nalmefene, and nalbuphine, involve removal ofthat naturally occurring opioid N-methyl group and its replacement withanother alkyl or an alkenyl moiety. The ultimate starting materials forpreparation of these semi-synthetic compounds include the naturalproducts morphine, codeine, thebaine, and oripavine. Among these,thebaine and oripavine are particularly useful because they are readilyoxidized to introduce the 14-hydroxyl group carried by each of the abovesemi-synthetic opiates. In a similar manner, the semi-syntheticprocesses for the synthesis of buprenorphine, levallorphan, pentazocine,cyclazocine, and ketazocine also involve replacement of an N-methylgroup of a tertiary amine with an alkyl or an alkenyl moiety. Synthesisof cabergoline from either lysergol or elymoclavine also involvesreplacement of a tertiary N-methyl group with an allyl moiety.

As described in the above references, the tertiary amine is converted toan intermediate that is subsequently cleaved to provide thecorresponding dealkylated (demethylated) secondary amine. The secondaryamine can then be realkylated, e.g., by condensation with an alkyl oralkenyl halide selected from among propyl iodide, cyclopropyl methylbromide, cyclobutyl methyl bromide, and allyl bromide (see, e.g., U.S.Pat. Nos. 3,905,981; 4,141,897; 3,254,088; 3,332,950; and 3,433,791).

However, these reactions can involve the use of materials and reagentsthat are relatively expensive, toxic and environmentally burdensome.Furthermore, the synthetic schemes disclosed generally involve threesteps for conversion of a tertiary amine to the corresponding N-allylderivative, as noted above. Such processes also may require purificationof intermediates, extended process times, and harsh reaction conditions,and may provide overall yields that are not commercially viable.

Accordingly, there remains a need for more efficient methods for thepreparation of N-allyl derivatives of tertiary amines, as well as forimproved processes incorporating those methods that would be robust,cost effective, amenable to commercial scale-up, and/or that wouldimpose lower burdens on the environment. In particular, there remains aneed for more efficient methods for preparing semi-synthetic opiatederivatives including, e.g., naloxone, naltrexone, nalmefene,nalbuphine, noroxymorphone, noroxycodone, and buprenorphine, as well aslevallorphan, pentazocine, cyclazocine, ketazocine, and cabergoline.

3. SUMMARY

The present disclosure provides methods for the preparation of N-allylcompounds from tertiary amines that involve conversion of the tertiaryamine to an allyl carbamate that is, in turn, decarboxylated in atransition metal-catalyzed reaction to provide the desired N-allylderivative. The present disclosure also provides methods for thepreparation of tertiary allyl amines from secondary amines.

In one embodiment, the tertiary amine is contacted with an allylhaloformate reagent to provide the allyl carbamate derivative directly.In other embodiments, the tertiary amine is contacted with certainhaloformate reagents to provide carbamate derivatives that are thenconverted to the corresponding allyl amine. As demonstrated below, thereactions and processes of the present disclosure are useful for thesynthesis of a variety of N-allyl compounds as well as derivatives ofthose compounds.

In certain embodiments, the present disclosure provides methods forconversion of oxymorphone to naloxone that include transitionmetal-catalyzed decarboxylation reactions. In other embodiments, thepresent disclosure provides methods for conversion of oxymorphone tonaltrexone that include transition metal-catalyzed decarboxylationreactions. In still other embodiments, the present disclosure providesmethods that include transition metal-catalyzed decarboxylationreactions that are useful for the conversion of oxymorphone tonoroxymorphone. In another embodiment, the present disclosure providesmethods for conversion of oxymorphone to buprenorphine that includetransition metal-catalyzed decarboxylation reactions.

In a specific embodiment, the reactions disclosed herein are used inprocesses through which oripavine, for example, is converted tonaloxone. In another specific application, the reactions disclosedherein are used in processes through which oripavine is converted tonaltrexone. In a further specific embodiment, the present disclosureprovides processes that include transition metal-catalyzeddecarboxylation reactions, for the preparation of noroxymorphone fromoripavine.

In a further embodiment, the present disclosure provides a method forthe conversion of naloxone to noroxymorphone.

In the embodiments involving a transition metal catalyst, the transitionmetal catalyst is present in an amount which enables the reaction toproceed. In certain embodiments, the transition metal catalyst ispresent in a sub-stoichiometric amount. In certain embodiments, thetransition metal catalyst is present in a catalytic amount. In certainembodiments, the transition metal catalyst is present in an amount offrom 0.001 to 30 mol % or of any numerical value within this range. Incertain embodiments, the transition metal catalyst is present in anamount of from 0.1 to 10 mol % or of any numerical value within thisrange (like about 5 mol %).

In one embodiment, therefore, the present disclosure provides a methodfor making a compound of formula (1)

comprising

(a) converting a compound of formula (2)

to a compound of formula (3)

and

(b) contacting the compound of formula (3) with a transition metalcatalyst to provide the compound of formula (1), where R¹, R², and R³are each independently selected from —(C₁-C₆)alkyl, —(C₂-C₆) alkenyl,and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynyl beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R¹ and R² are taken together withthe nitrogen atom to which they are bound to form a heterocyclic orheteroaryl ring of formula (5)

where n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R⁶ and R⁷ are taken together withthe carbon atoms to which each is bound to form a carbocyclic ring of 3,4, 5, 6, 7, 8, or 9 carbon atoms, the carbocyclic ring beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I, phenyl,or —(C₁-C₆) alkyl; and R⁵¹ is —(C₁-C₆) alkyl or an oxygen protectinggroup. In certain embodiments, R⁶ and R⁷ are taken together with thecarbon atoms to which each is bound to form a carbocyclic ring of 3, 4,5, or 6 carbon atoms, the carbocyclic ring being unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups; R⁸is —OR⁵¹, —F, —Cl, —Br, —I, phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is—(C₁-C₆) alkyl or an oxygen protecting group.

The heterocyclic or heteroaryl ring of formula (5) is a monocyclic ringthat is saturated, unsaturated non-heteroaryl, or heteroaryl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁵² groups, or is a subunit of a polycyclic ringsystem comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic,heterocyclic, aryl, or heteroaryl rings, each of which is unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups.R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, —C(═O)(C₁-C₆)alkyl, and —(C₁-C₆) alkyl, where each alkyl group is eitherunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected —OR⁵³ groups; and R⁵³ is —H or an oxygenprotecting group. In certain embodiments, R⁵² is selected from ═O, ═CH₂,—OR⁵³, —O(C₁-C₆) alkyl, and —(C₁-C₆) alkyl, where each alkyl group iseither unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected —OR⁵³ groups; and R⁵³ is —H or an oxygenprotecting group.

In certain embodiments, at least one of R¹, R², and R³ of the tertiaryamine of formula (2) is —(C₁-C₆)alkyl. In certain embodiments, R³ is—(C₁-C₆)alkyl. In certain embodiments, at least one of R¹, R², and R³ ofthe tertiary amine of formula (2) is methyl. In certain embodiments, R³is methyl.

In certain embodiments, the transition metal catalyst is present in asub-stoichiometric amount. In certain embodiments, the transition metalcatalyst is present in a catalytic amount. In certain embodiments, thetransition metal catalyst is present in an amount of from 0.001 to 30mol % or of any numerical value within this range. In certainembodiments, the transition metal catalyst is present in an amount offrom 0.1 to 10 mol % or of any numerical value within this range (likeabout 5 mol %).

In another embodiment, the present disclosure provides a method formaking a compound of formula (1)

comprising

(a) converting a compound of formula (2)

to a compound of formula (3)

and

(b) decarboxylating the compound of formula (3) to provide the compoundof formula (1), where R¹, R², and R³ are each independently selectedfrom —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl,alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4,or 5 independently-selected R⁸ groups, or R¹ and R² are taken togetherwith the nitrogen atom to which they are bound to form a heterocyclic orheteroaryl ring of formula (5)

where n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R⁶ and R⁷ are taken together withthe carbon atoms to which each is bound to form a carbocyclic ring of 3,4, 5, 6, 7, 8, or 9 carbon atoms, the carbocyclic ring beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I, phenyl,or —(C₁-C₆) alkyl; and R⁵¹ is —(C₁-C₆) alkyl or an oxygen protectinggroup. In certain embodiments, R⁶ and R⁷ are taken together with thecarbon atoms to which each is bound to form a carbocyclic ring of 3, 4,5, or 6 carbon atoms, the carbocyclic ring being unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups; R⁸is —OR⁵¹, —F, —Cl, —Br, —I, phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is—(C₁-C₆) alkyl or an oxygen protecting group.

The heterocyclic or heteroaryl ring of formula (5) is a monocyclic ringthat is saturated, unsaturated non-heteroaryl, or heteroaryl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁵² groups, or is a subunit of a polycyclic ringsystem comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic,heterocyclic, aryl, or heteroaryl rings, each of which is unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups.R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, —C(═O)(C₁-C₆)alkyl, and —(C₁-C₆) alkyl, where each alkyl group is eitherunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected —OR⁵³ groups; and R⁵³ is —H or an oxygenprotecting group. In certain embodiments, R⁵² is selected from ═O, ═CH₂,—OR⁵³, —O(C₁-C₆) alkyl, and —(C₁-C₆) alkyl, where each alkyl group iseither unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected —OR⁵³ groups; and R⁵³ is —H or an oxygenprotecting group.

In certain embodiments, the compound of formula (3) is formed by addinga compound of formula (2) to a compound of formula (93)

in a suitable solvent, where R′, R², R³, R⁴, R⁵, and R⁶ and R⁷ are asdefined above and X is selected from —Cl, —Br, and —I. The reaction ofthe compound of formula (2) to the compound of formula (93) can becarried out in the presence of a base.

In particular embodiments, a stoichiometric excess of the compound offormula (93)

is added relative to the compound of formula (2)

to provide the compound of formula (3), where R¹, R², R³, R⁴, R⁵, R⁶,and X are defined as above. The compound of formula (93) can be added intotal at the beginning of the reaction or can be added in a plurality ofportions, i.e., portion-wise, throughout the course of the reaction. Incertain embodiments, the compound of formula (93) is added continuouslythroughout the course of the reaction.

The conversion of a compound of formula (2) to a compound of formula (3)can be carried out in any suitable solvent in which the reaction canproceed. In certain embodiments, the solvent is selected from the groupconsisting of ether solvents, acetonitrile, benzene,N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N,N-dimethylpropionamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxyethane (DME),N,N-dimethylacetamide (DMAC), N-methylpyrrolidinone (NMP), ethylacetate, ethyl formate, ethyl-methyl ketone, iso-butylmethylketone,formamide, hexamethylphosphoramide, methyl acetate, N-methylacetamide,N-methylformamide, nitrobenzene, nitromethane, propionitrile, sulfolane,tetramethylurea, tetrahydrofuran (THF), toluene, CHCl₃, CH₂Cl₂,1,2-dichloroethane, acetone, tert-amyl alcohol, tert-butyl alcohol,3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol,2-methyl-2-hexanol, acetonitrile, benzene, carbon tetrachloride,chlorobenzene, 1,2-dichlorobenzene, DMF, trifluorotoluene, 1,4-dioxane,1,2-dimethoyxethane, xylene, and combinations of two or more thereof.

In particular embodiments, the solvent comprises, consists essentially,or is (i.e., consists of) a tertiary alcohol selected from the groupconsisting of tert-amyl alcohol, tert-butyl alcohol,3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol,2-methyl-2-hexanol, and combinations of two or more thereof. In aspecific embodiment, the solvent comprises tert-amyl alcohol. In anotherspecific embodiment, the solvent consists essentially of tert-amylalcohol. In another specific embodiment, the solvent is tert-amylalcohol.

In other embodiments, in particular in embodiments regarding theheterocyclic or heteroaryl ring of formula (5), the conversion of acompound of formula (2) to a compound of formula (3) is carried out inthe presence of an iodide salt. In certain embodiments, the iodide saltis present in a sub-stoichiometric amount. In certain embodiments, theiodide salt is present in a catalytic amount. The iodide salt isselected from the group consisting of NaI, KI, LiI, CsI, RuI, MgI₂,CaI₂, NH₄I, tetrabutylammonium iodide, and combinations of two or morethereof. In certain embodiments, the iodide salt is NaI.

In certain embodiments, n is an integer selected from 0, 1, 2, 3, 4, 5,6, 7, 8, and 9. In certain other embodiments, n is an integer selectedfrom 0, 1, 2, 3, 4, 5, 6, and 7. In further embodiments, n is an integerselected from 0, 1, 2, 3, 4, and 5. In a particular embodiment, n is aninteger selected from 0, 1, 2, and 3. In another particular embodiment,n is 3.

In another embodiment, the present disclosure provides a method formaking a compound of formula (1)

comprising contacting a compound of formula (2)

with a compound of formula (23)

and a base in a solvent to provide a compound of formula (24)

and contacting the compound of formula (24) with a transition metalcatalyst to provide the compound of formula (1), where R¹, R², and R³are each independently selected from —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl,and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynyl beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R¹ and R² are taken together withthe nitrogen atom to which they are bound to form a heterocyclic orheteroaryl ring of formula (5)

where n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; X is selected from —Cl, —Br, and —I; R⁴ is selected from thegroup consisting of —H, —(C₁-C₆) alkyl, phenyl, allyl, -2-butenyl,-3-butenyl, -4-pentenyl, -2-propynyl, -2-butynyl, -3-butynyl,-2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I, phenyl,or —(C₁-C₆) alkyl; R⁵¹ is —(C₁-C₆) alkyl or an oxygen protecting group;and V is a leaving group.

In certain other embodiments, n is an integer selected from 0, 1, 2, 3,4, 5, 6, and 7. In further embodiments, n is an integer selected from 0,1, 2, 3, 4, and 5. In a particular embodiment, n is an integer selectedfrom 0, 1, 2, and 3. In another particular embodiment, n is 3.

The heterocyclic or heteroaryl ring of formula (5) is a monocyclic ringthat is saturated, unsaturated non-heteroaryl, or heteroaryl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁵² groups, or is a subunit of a polycyclic ringsystem comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic,heterocyclic, aryl, or heteroaryl rings, each of which is unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups.R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, —C(═O)(C₁-C₆)alkyl, and —(C₁-C₆) alkyl, each alkyl group being either unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³groups; and R⁵³ is —H or an oxygen protecting group. In certainembodiments, R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, and—(C₁-C₆) alkyl, where each alkyl group is either unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³ groups;and R⁵³ is —H or an oxygen protecting group.

In certain embodiments, the transition metal catalyst is present in asub-stoichiometric amount. In certain embodiments, the transition metalcatalyst is present in a catalytic amount. In certain embodiments, thetransition metal catalyst is present in an amount of from 0.001 to 30mol % or of any numerical value within this range. In certainembodiments, the transition metal catalyst is present in an amount offrom 0.1 to 10 mol % or of any numerical value within this range (likeabout 5 mol %).

In another embodiment, the present disclosure provides a method formaking a compound of formula (1)

comprising contacting a compound of formula (25)

with a compound of formula (26)

in a solvent comprising a transition metal catalyst to provide thecompound of formula (1), where R¹ and R² are independently selected from—(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl,alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4,or 5 independently-selected R⁸ groups, or R¹ and R² are taken togetherwith the nitrogen atom to which they are bound to form a heterocyclic orheteroaryl ring of formula (5)

where n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl.

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R⁶ and R⁷ are taken together withthe carbon atoms to which each is bound to form a carbocyclic ring of 3,4, 5, 6, 7, 8, or 9 carbon atoms, the carbocyclic ring beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I, phenyl,or —(C₁-C₆) alkyl; and R⁵¹ is —(C₁-C₆) alkyl or an oxygen protectinggroup. In certain embodiments, R⁶ and R⁷ are taken together with thecarbon atoms to which each is bound to form a carbocyclic ring of 3, 4,5, or 6 carbon atoms, the carbocyclic ring being unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups; R⁸is —OR⁵¹, —F, —Cl, —Br, —I, phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is—(C₁-C₆) alkyl or an oxygen protecting group.

In certain other embodiments, n is an integer selected from 0, 1, 2, 3,4, 5, 6, and 7. In further embodiments, n is an integer selected from 0,1, 2, 3, 4, and 5. In a particular embodiment, n is an integer selectedfrom 0, 1, 2, and 3. In another particular embodiment, n is 3.

The heterocyclic or heteroaryl ring of formula (5) is a monocyclic ringthat is saturated, unsaturated non-heteroaryl, or heteroaryl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁵² groups, or is a subunit of a polycyclic ringsystem comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic,heterocyclic, aryl, or heteroaryl rings, each of which is unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups.R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O (C₁-C₆) alkyl, —C(═O)(C₁-C₆)alkyl, and —(C₁-C₆) alkyl, each alkyl group being either unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³groups; and R⁵³ is —H or an oxygen protecting group. In certainembodiments, R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, and—(C₁-C₆) alkyl, where each alkyl group is either unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³ groups;and R⁵³ is —H or an oxygen protecting group.

In certain embodiments, R⁴⁰ is selected from —OC(O)CH₃ and —N(CH₃)₂while, in other embodiments, R⁴⁰ is —O(C)OX and X is —Cl, —Br, or —I.

In one embodiment, the compound of formula (25) is contacted with acompound of formula (23)

in a solvent in the presence of a transition metal catalyst to provide acompound of formula (1). X, R⁴, R⁵, R⁶, R⁷, and V are as defined above.In one aspect of this embodiment, the contacting is done in the presenceof a base.

In another embodiment, the compound of formula (25) is contacted with acompound of formula (48)

and a transition metal catalyst to provide a compound of formula (1).

In another embodiment, the compound of formula (25) is contacted with acompound of formula (46)

and a transition metal catalyst to provide a compound of formula (1). Xis selected from —Cl, —Br, and —I. Y is a leaving group. In certainembodiments, the contacting of the compound of formula (25) with thecompound of formula (46) is carried out under condition or in thepresence of a reagent that promotes elimination of the leaving group, Y.In one aspect of this embodiment, the reagent is a base. Where thereagent is a base, it can, for example, be selected from the groupconsisting of NaOH, KOH, sodium tert-butoxide (tert-BuONa), potassiumtert-butoxide (tert-BuOK), lithium di-iso-propylamide, sodium hydride,tert-butyl lithium, LiAlH₄, AlCl₃, triethylamine, sodium ethoxide,lithium diethyl amide (LiN(Et)₂), potassium acetate (KOAc), andcombinations of two or more thereof. The reagent can also be, e.g.,ethylmagnesium bromide and tributyltin hydride, in particular wherethere are two leaving groups which are both —Br. In another aspect,elimination of the leaving group Y is promoted by heat. In a furtheraspect, elimination of the leaving group Y is promoted by exposure tolight of an appropriate wavelength.

In a further embodiment, the compound of formula (25) is contacted witha compound of formula (19)

and a transition metal catalyst to provide a compound of formula (27)

In another embodiment, the compound of formula (25) is contacted with acompound of formula (29)

and a transition metal catalyst to provide a compound of formula (27)

Each X is independently selected from —Cl, —Br, and —I. R¹, R², R⁴, andR⁵ are as defined above; p is an integer selected from 1, 2, 3, 4, 5, 6,and 7.

Accordingly, the present disclosure further provides a method for makinga compound of formula (27)

comprising

(a) contacting a compound of formula (2)

with a compound of formula (19)

to provide a compound of formula (18)

(b) contacting the compound of formula (18) with a transition metalcatalyst to provide a compound of formula (17)

and

(c) hydrogenating the compound of formula (17), to provide the compoundof formula (27), where R′, R², and R³ are each independently selectedfrom —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl,alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4,or 5 independently-selected R⁸ groups, or R¹ and R² are taken togetherwith the nitrogen atom to which they are bound to form a heterocyclic orheteroaryl ring of formula (5)

where n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; and X is selected from —Cl, —Br, and —I; R⁵ is selected from —H,—(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl,alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4,or 5 independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I,phenyl, or —(C₁-C₆) alkyl; R⁵¹ is —(C₁-C₆) alkyl or an oxygen protectinggroup; and p is an integer selected from 1, 2, 3, 4, 5, 6, and 7.

In certain other embodiments, n is an integer selected from 0, 1, 2, 3,4, 5, 6, and 7. In further embodiments, n is an integer selected from 0,1, 2, 3, 4, and 5. In a particular embodiment, n is an integer selectedfrom 0, 1, 2, and 3. In another particular embodiment, n is 3.

The heterocyclic or heteroaryl ring of formula (5) is a monocyclic ringthat is saturated, unsaturated non-heteroaryl, or heteroaryl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁵² groups, or is a subunit of a polycyclic ringsystem comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic,heterocyclic, aryl, or heteroaryl rings, each of which is unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups.R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O (C₁-C₆) alkyl, —C(═O)(C₁-C₆)alkyl, and —(C₁-C₆) each alkyl either being unsubstituted or substitutedwith 1, 2, 3, 4, or 5 independently-selected —OR⁵³ groups; and R⁵³ is —Hor an oxygen protecting group. In certain embodiments, R⁵² is selectedfrom ═O, ═CH₂, —OR⁵³, —O (C₁-C₆) alkyl, and —(C₁-C₆) alkyl, where eachalkyl group is either unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected —OR⁵³ groups; and R⁵³ is —H or an oxygenprotecting group.

The present disclosure also provides a method for making a compound offormula (28)

comprising

(a) contacting a compound of formula (2)

with a compound of formula (29)

to provide a compound of formula (30)

(b) contacting the compound of formula (30) with a transition metalcatalyst to provide a compound of formula (31)

and

(c) contacting the compound of formula (31) with a zinc-containingreagent, e.g., zinc[0], in the presence of an iodide salt to provide thecompound of formula (28), where R′, R², and R³ are each independentlyselected from —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl,each alkyl, alkenyl, and alkynyl being unsubstituted or substituted with1, 2, 3, 4, or 5 independently-selected R⁸ groups, or R¹ and R² aretaken together with the nitrogen atom to which they are bound to form aheterocyclic or heteroaryl ring of formula (5)

where n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; X is selected from —Cl, —Br, and —I; R⁴ is selected from thegroup consisting of —H, —(C₁-C₆) alkyl, phenyl, allyl, -2-butenyl,-3-butenyl, -4-pentenyl, -2-propynyl, -2-butynyl, -3-butynyl,-2-pentynyl,

R⁸ is —OR⁵¹, —F, —Cl, —Br, —I, phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is—(C₁-C₆) alkyl or an oxygen protecting group.

In certain other embodiments, n is an integer selected from 0, 1, 2, 3,4, 5, 6, and 7. In further embodiments, n is an integer selected from 0,1, 2, 3, 4, and 5. In a particular embodiment, n is an integer selectedfrom 0, 1, 2, and 3. In another particular embodiment, n is 3.

The heterocyclic or heteroaryl ring of formula (5) is a monocyclic ringthat is saturated, unsaturated non-heteroaryl, or heteroaryl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁵² groups, or is a subunit of a polycyclic ringsystem comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic,heterocyclic, aryl, or heteroaryl rings, each of which is unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups.R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, —C(═O)(C₁-C₆)alkyl, and —(C₁-C₆) alkyl, each alkyl group being either unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵3groups; and R⁵³ is —H or an oxygen protecting group. In certainembodiments, R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, and—(C₁-C₆) alkyl, where each alkyl group is either unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³ groups;and R⁵³ is —H or an oxygen protecting group.

In certain embodiments, the iodide salt is present in asub-stoichiometric amount. In certain embodiments, the iodide salt ispresent in a catalytic amount. In certain embodiments, the iodide saltcan be selected from, e.g., NaI, KI, LiI, CsI, RuI, MgI₂, CaI₂, NH₄I,tetrabutylammonium iodide, and combinations of two or more thereof. Incertain embodiments, the iodide salt is NaI.

The present disclosure also provides a method for making a compound offormula (32)

comprising

(a) converting a compound of formula (2)

to a compound of formula (3)

(b) contacting the compound of formula (3) with a transition metalcatalyst to provide a compound of formula (1)

and

(c) converting the compound of formula (1) to the compound of formula(32), where R¹, R², and R³ are each independently selected from —(C₁-C₆)alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, andalkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R¹ and R² are taken together withthe nitrogen atom to which they are bound to form a heterocyclic orheteroaryl ring of formula (5)

where n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I, phenyl,or —(C₁-C₆) alkyl; R⁵¹ is —(C₁-C₆) alkyl or an oxygen protecting group;W is CH₂, 0, or NR⁴¹; R⁴¹ is selected from —H, tert-butyl,—CH₂CH₂OCH₂CH₃, —C(O)OCH₃, —P(O)(OCH₂CH₃)₂, phthalimide, and —S(O)₂Z;and Z is selected from tert-butyl, phenyl, toluyl, para-methoxyphenyl,ortho-nitrophenyl, 2,4,6-trimethylphenyl, and —CH₂CH₂Si(CH₃)₃.

In certain other embodiments, n is an integer selected from 0, 1, 2, 3,4, 5, 6, and 7. In further embodiments, n is an integer selected from 0,1, 2, 3, 4, and 5. In a particular embodiment, n is an integer selectedfrom 0, 1, 2, and 3. In another particular embodiment, n is 3.

The heterocyclic or heteroaryl ring of formula (5) is a monocyclic ringthat is saturated, unsaturated non-heteroaryl, or heteroaryl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁵² groups, or is a subunit of a polycyclic ringsystem comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic,heterocyclic, aryl, or heteroaryl rings, each of which is unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups.R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, —C(═O)(C₁-C₆)alkyl, and —(C₁-C₆) alkyl, each alkyl being either unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³ groups;and R⁵³ is —H or an oxygen protecting group. In certain embodiments, R⁵²is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, and —(C₁-C₆) alkyl,where each alkyl group is either unsubstituted or substituted with 1, 2,3, 4, or 5 independently-selected —OR⁵³ groups; and R⁵³ is —H or anoxygen protecting group.

In a further embodiment, the present disclosure provides a method formaking a compound of formula (39)

comprising

(a) converting a compound of formula (2)

to a compound of formula (3)

(b) contacting the compound of formula (3) with a transition metalcatalyst to provide a compound of formula (1)

and

(c) hydrogenating the compound of formula (1) to provide the compound offormula (39), where R¹, R², and R³ are each independently selected from—(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl,alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4,or 5 independently-selected R⁸ groups, or R¹ and R² are taken togetherwith the nitrogen atom to which they are bound to form a heterocyclic orheteroaryl ring of formula (5)

where n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R⁶ and R⁷ are taken together withthe carbon atoms to which each is bound to form a carbocyclic ring of 3,4, 5, 6, 7, 8, or 9 carbon atoms, the carbocyclic ring beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I, phenyl,or —(C₁-C₆) alkyl; and R⁵¹ is —(C₁-C₆) alkyl or an oxygen protectinggroup. In certain embodiments, R⁶ and R⁷ are taken together with thecarbon atoms to which each is bound to form a carbocyclic ring of 3, 4,5, or 6 carbon atoms, the carbocyclic ring being unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups; R⁸is —OR⁵¹, —F, —Cl, —Br, —I, phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is—(C₁-C₆) alkyl or an oxygen protecting group.

In certain other embodiments, n is an integer selected from 0, 1, 2, 3,4, 5, 6, and 7. In further embodiments, n is an integer selected from 0,1, 2, 3, 4, and 5. In a particular embodiment, n is an integer selectedfrom 0, 1, 2, and 3. In another particular embodiment, n is 3.

The heterocyclic or heteroaryl ring of formula (5) is a monocyclic ringthat is saturated, unsaturated non-heteroaryl, or heteroaryl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁵² groups, or is a subunit of a polycyclic ringsystem comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic,heterocyclic, aryl, or heteroaryl rings, each of which is unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups.R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, —C(═O)(C₁-C₆)alkyl, and —(C₁-C₆) alkyl, each alkyl being either unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³ groups;and R⁵³ is —H or an oxygen protecting group. In certain embodiments, R⁵²is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, and —(C₁-C₆) alkyl,where each alkyl group is either unsubstituted or substituted with 1, 2,3, 4, or 5 independently-selected —OR⁵³ groups; and R⁵³ is —H or anoxygen protecting group.

In another embodiment, the disclosure provides a method for making acompound of formula (40)

comprising

(a) converting a compound of formula (2)

to a compound of formula (3)

(b) contacting the compound of formula (3) with a transition metalcatalyst to provide a compound of formula (1)

and

(c) oxidizing the compound of formula (1) to provide the compound offormula (40), where R′, R², and R³ are each independently selected from—(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl,alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4,or 5 independently-selected R⁸ groups, or R¹ and R² are taken togetherwith the nitrogen atom to which they are bound to form a heterocyclic orheteroaryl ring of formula (5)

where n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R⁶ and R⁷ are taken together withthe carbon atoms to which each is bound to form a carbocyclic ring of 3,4, 5, 6, 7, 8, or 9 carbon atoms, the carbocyclic ring beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I, phenyl,or —(C₁-C₆) alkyl; and R⁵¹ is —(C₁-C₆) alkyl or an oxygen protectinggroup. In certain embodiments, R⁶ and R⁷ are taken together with thecarbon atoms to which each is bound to form a carbocyclic ring of 3, 4,5, or 6 carbon atoms, the carbocyclic ring being unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups; R⁸is —OR⁵¹, —F, —Cl, —Br, —I, phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is—(C₁-C₆) alkyl or an oxygen protecting group.

In certain other embodiments, n is an integer selected from 0, 1, 2, 3,4, 5, 6, and 7. In further embodiments, n is an integer selected from 0,1, 2, 3, 4, and 5. In a particular embodiment, n is an integer selectedfrom 0, 1, 2, and 3. In another particular embodiment, n is 3.

The heterocyclic or heteroaryl ring of formula (5) is a monocyclic ringthat is saturated, unsaturated non-heteroaryl, or heteroaryl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁵² groups, or is a subunit of a polycyclic ringsystem comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic,heterocyclic, aryl, or heteroaryl rings, each of which is unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups.R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, —C(═O)(C₁-C₆)alkyl, and —(C₁-C₆) alkyl, each alkyl being either unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³ groups;and R⁵³ is —H or an oxygen protecting group. In certain embodiments, R⁵²is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, and —(C₁-C₆) alkyl,where each alkyl group is either unsubstituted or substituted with 1, 2,3, 4, or 5 independently-selected —OR⁵³ groups; and R⁵³ is —H or anoxygen protecting group.

The methods disclosed herein are readily adapted for the synthesis ofclinically and commercially important compounds including, but notlimited to, naloxone, naltrexone, noroxymorphone, noroxycodone,buprenorphine, and cabergoline. In particular embodiments, the methodsdisclosed herein are useful for specific conversions, e.g., thepreparation of naloxone from oxymorphone, and for incorporation intooverall processes, e.g., the preparation of naloxone from oripavine. Themethods disclosed herein are also readily adapted to the synthesis ofsuch clinically and commercially important compounds from morphine,codeine, and thebaine.

Therefore, in another embodiment, the present disclosure provides amethod for making a compound of formula (41)

comprising contacting a compound of formula (42)

with a transition metal catalyst in a solvent to provide the compound offormula (41), where R¹⁴ and R¹⁶ are each independently selected from—OH, —H, and —OR¹⁷; R¹⁵ is selected from —OH, —H, —OR¹⁷, ═O, and ═CH₂,and R¹⁷ is an oxygen protecting group.

In another aspect of this embodiment, the preceding method furthercomprises reacting a compound of formula (45)

with a compound of formula (48)

in a solvent comprising a base to provide the compound of formula (95)

where R¹⁴ and R¹⁶ are each independently selected from —OH, —H, and—OR¹⁷; R¹⁵ is selected from —OH, —H, —OR¹⁷, ═O, and ═CH₂; R¹⁷ is anoxygen protecting group; and X is selected from —Cl, —Br, and —I.

As used throughout herein, it is to be understood that R^(14′), R^(15′),and R^(16′) include not only R¹⁴, R¹⁵, and R¹⁶, respectively, but also,when an R¹⁴, R¹⁵, and/or R¹⁶ group is present as an —OH group orcontains an —OH group, the reaction product of a compound of formula(48) or its equivalent, e.g., an “allyl haloformate equivalent,” withthat —OH group to form a group comprising a carbonate. Thus, R^(14′),R^(15′), and R^(16′) groups include, in addition to the respective R¹⁴,R¹⁵, and R¹⁶ groups, such carbonate-containing reaction products. Evenfurther, certain reaction pathways described herein convert thecarbonate portion of the carbonate-containing reaction product into anether group. Thus, R^(14′), R^(15′), and R^(16′) further include suchether-containing reaction products.

It is also to be understood that when R¹⁴ is selected to be a particularmoiety that is not an —OH group, then R^(14′) is also that particularR¹⁴ moiety. Likewise, it is to be understood that when R¹⁵ is selectedto be a particular moiety that is not an —OH group, then R^(15′) is alsothat particular R¹⁵ moiety. Likewise, it is to be understood that whenR¹⁶ is selected to be a particular moiety that is not an —OH group, thenR^(16′) is also that particular R¹⁶ moiety.

In embodiments where an R^(14′), R^(15′), and/or R^(16′) group(s) is orcontains a carbonate-containing group formed from an —OH group, thatcarbonate-containing group can be converted back to the —OH group.Conversion of the carbonate-containing group to the —OH group can becarried out in the presence of a suitable base. Alternatively, when anR^(14′), R^(15′), and/or R^(16′) group is an allyl carbonate, that allylcarbonate can first be converted into an —O-allyl group through atransition metal catalyzed decarboxylation reaction, in accordance withthe present disclosure. Thereafter, the —O-allyl group can be convertedinto an —OH group in the presence of a suitable allyl scavenger, asdescribed herein.

The reaction of the compound of formula (45) with a compound of formula(48) can be carried out in any suitable solvent in which the reactioncan proceed. In certain embodiments, the solvent is selected from thegroup consisting of ether solvents, acetonitrile, benzene, DMF, DMSO,N,N-dimethylpropionamide, DMPU, DMI, DME, DMAC, NMP, ethyl acetate,ethyl formate, ethyl-methyl ketone, iso-butylmethylketone, formamide,hexamethylphosphoramide, methyl acetate, N-methylacetamide,N-methylformamide, nitrobenzene, nitromethane, propionitrile, sulfolane,tetramethylurea, THF, toluene, CHCl₃, CH₂Cl₂, 1,2-dichloroethane, THF,acetone, tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol,2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol,acetonitrile, benzene, carbon tetrachloride, chlorobenzene,1,2-dichlorobenzene, DMF, trifluorotoluene, 1,4-dioxane,1,2-dimethoyxethane, xylene, and combinations of two or more thereof.

In particular embodiments, the solvent comprises, consists essentially,or is (i.e., consists of) a tertiary alcohol selected from the groupconsisting of tert-amyl alcohol, tert-butyl alcohol,3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol,2-methyl-2-hexanol, and combinations of two or more thereof. In aspecific embodiment, the solvent comprises tert-amyl alcohol. In anotherspecific embodiment, the solvent consists essentially of tert-amylalcohol. In another specific embodiment, the solvent is tert-amylalcohol.

In other embodiments, the reaction of the compound of formula (45) withthe compound of formula (48) is carried out in the presence of an iodidesalt. In certain embodiments, the iodide salt is present in asub-stoichiometric amount. In certain embodiments, the iodide salt ispresent in a catalytic amount. The iodide salt is selected from thegroup consisting of NaI, KI, LiI, CsI, RuI, MgI₂, CaI₂, NH₄I,tetrabutylammonium iodide, and combinations of two or more thereof. Incertain embodiments, the iodide salt is NaI.

In other embodiments, a stoichiometric excess of the compound of formula(48) is added relative to the compound of formula (45) to provide acompound of formula (95). The compound of formula (48) can be added intotal at the beginning of the reaction or portion-wise throughout thecourse of the reaction (e.g., see Examples 3 and 18 below). In certainembodiments, the compound of formula (48) is added continuouslythroughout the course of the reaction.

The present disclosure also provides for an alternative method of makinga compound of formula (41)

which comprises

(a) reacting a compound of formula (45)

with a compound of formula (46)

to provide a compound of formula (47)

(b) optionally, converting the compound of formula (47) to the compoundof formula (94)

(c) converting the compound of formula (47) or the compound of formula(94) to a compound of formula (42)

and

(d) converting the compound of formula (42) to the compound of formula(41), where R¹⁴, R^(14′), R¹⁵, R^(15′), R¹⁶, R^(16′), X, and Y aredefined as above.

In one embodiment, the reacting of the compound of formula (45) with thecompound of formula (46) is carried out in the presence of a base.

In another embodiment, the converting of the compound of formula (47) orthe compound of formula (94) to a compound of formula (42) is carriedout under conditions and/or in the presence of a reagent that promoteselimination of the leaving group, Y. In one aspect of this embodiment,the reagent is a base. Where the reagent is a base, it can, for example,be selected from the group consisting of NaOH, KOH, sodium tert-butoxide(tert-BuONa), potassium tert-butoxide (tert-BuOK), lithiumdi-iso-propylamide, sodium hydride, tert-butyl lithium, LiAlH₄, AlCl₃,triethylamine, sodium ethoxide, lithium diethyl amide (LiN(Et)₂),potassium acetate (KOAc), and combinations of two or more thereof. Thereagent can also be, e.g., ethylmagnesium bromide and tributyltinhydride, in particular where there are two leaving groups which are both—Br. In another aspect, elimination of the leaving group Y is promotedby heat. In a further aspect, elimination of the leaving group Y ispromoted by exposure to light of an appropriate wavelength.

In particular embodiments of the above methods, the compound of formula(45) is a compound of formula (51)

which can be prepared by oxidizing a compound of formula (52)

to provide a compound of formula (53)

and hydrogenating the compound of formula (53) to provide the compoundof formula (51). In certain embodiments of this method, R¹⁴ is —OHwhile, in other embodiments, R¹⁴ is —OCH₃.

The present disclosure also provides a method for making a compound offormula (54)

comprising contacting a compound of formula (55)

with a compound of formula (56)

in a solvent comprising a base and a transition metal catalyst toprovide the compound of formula (54), where R¹⁴ and R¹⁶ are eachindependently selected from —OH, —H, and —OR¹⁷; the 6,7

bond, the 7,8

bond, and the 8,14

bond are each independently a single bond or a double bond, with theprovisos that (1) if the 6,7

bond is a double bond, then the 7,8

bond is a single bond, (2) if the 7,8

bond is a double bond, then the 6,7

and 8,14

bonds are each a single bond, and (3) if the 8,14

bond is a double bond, then the 7,8

bond is a single bond and R¹⁶ is not present. R¹⁵ is selected from —OH,—H, —OR¹⁷, ═O, and ═CH₂ with the proviso that if the 6,7

bond is a double bond, then R¹⁵ is selected from —OH, —H, and —OR¹⁷; andR¹⁷ is an oxygen protecting group. R²² is selected from —N(CH₃)₂,—OC(O)CH₃, and —OC(O)X; and X is selected from —Cl, —Br, and —I. In oneembodiment, R²² is selected from —N(CH₃)₂ and —OC(O)CH₃. In anotherembodiment, R²² is —OC(O)X.

In other embodiments, the compound of formula (54) can be prepared bycontacting the compound of formula (55) with a compound of formula (46)in the presence of a transition metal catalyst. In other embodiments,the compound of formula (54) can be prepared by contacting the compoundof formula (55) with a compound of formula (48) in the presence of atransition metal catalyst.

In another specific aspect, the present disclosure also provides amethod for making a compound of formula (57)

comprising contacting a compound of formula (42)

with a transition metal catalyst in the presence of an allyl scavenger,to provide the compound of formula (57), where R¹⁴ and R¹⁶ are eachindependently selected from —OH, —H, and —OR¹⁷; R¹⁵ is selected from—OH, —H, —OR¹⁷, ═O, and ═CH₂; and R¹⁷ is an oxygen protecting group.

In one embodiment, the allyl scavenger can be selected from those knownin the art, e.g., from among the following illustrative examples:

and combinations of two or more thereof. In another embodiment, theallyl scavenger can be selected from the group consisting of sodium2-ethylhexonate, morpholine, dimedone, 4-methylbenzensulfinic acid,sodium hydroxymethyl sulfinate, benzenesulfinic acid, sodium toluenesulfinate, sodium 2-thiophene sulfinate, tetrabutylammonium toluenesulfinate, N,N-dimethyl barbituric acid, sodium 4-chloro-3-nitrobenzenesulfinate, formic acid, diethyl amine, methanol, ethanol, andcombinations of two or more thereof. In another embodiment, the allylscavenger is compound (146)

The present disclosure also provides a method for making a compound offormula (62)

comprising

(a) contacting a compound of formula (45)

with a compound of formula (63)

in a solvent comprising a base to provide a compound of formula (64)

(b) optionally, converting the carbonate groups present at R^(14′),R^(15′), and R^(16′) to —OH groups to provide a compound of formula (96)

(c) contacting the compound of formula (64) or the compound of formula(96) with a transition metal catalyst to provide a compound of formula(65)

and

(d) hydrogenating the compound of formula (65) to provide the compoundof formula (62), where R¹⁴, R^(14′), R¹⁵, R^(15′), R¹⁶, R^(16′) and Xare defined as above and p is an integer selected from 1, 2, 3, 4, 5, 6,and 7.

In another embodiment, the present disclosure provides a method formaking a compound of formula (66)

the method comprising

(a) contacting a compound of formula (45)

with a compound of formula (67)

in a solvent comprising a base to provide a compound of formula (68)

(b) optionally, converting the carbonate groups present at R^(14′),R^(15′), and R^(16′) to —OH groups to provide a compound of formula (97)

(c) contacting the compound of formula (68) or the compound of formula(97) with a transition metal catalyst to provide a compound of formula(69)

and

(d) contacting the compound of formula (69) with a zinc-containingreagent, e.g., zinc[0], in the presence of an iodide salt to provide thecompound of formula (66), where R¹⁴, R^(14′), R¹⁵, R^(15′), R¹⁶,R^(16′), and X are defined as above.

The reaction of the compound of formula (45) with a compound of formula(63) or with a compound of formula (67) can be carried out in anysuitable solvent in which the reaction can proceed. In certainembodiments, the solvent is selected from the group consisting of ethersolvents, acetonitrile, benzene, DMF, DMSO, N,N-dimethylpropionamide,DMPU, DMI, DME, DMAC, NMP, ethyl acetate, ethyl formate, ethyl-methylketone, iso-butylmethylketone, formamide, hexamethylphosphoramide,methyl acetate, N-methylacetamide, N-methylformamide, nitrobenzene,nitromethane, propionitrile, sulfolane, tetramethylurea, THF, toluene,CHCl₃, CH₂Cl₂, 1,2-dichloroethane, THF, acetone, tert-amyl alcohol,tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol,3-ethyl pentanol, 2-methyl-2-hexanol, acetonitrile, benzene, carbontetrachloride, chlorobenzene, 1,2-dichlorobenzene, DMF,trifluorotoluene, 1,4-dioxane, 1,2-dimethoyxethane, xylene, andcombinations of two or more thereof.

In particular embodiments, the solvent comprises, consists essentially,or is (i.e., consists of) a tertiary alcohol selected from the groupconsisting of tert-amyl alcohol, tert-butyl alcohol,3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol,2-methyl-2-hexanol, and combinations of two or more thereof. In aspecific embodiment, the solvent comprises tert-amyl alcohol. In anotherspecific embodiment, the solvent consists essentially of tert-amylalcohol. In another specific embodiment, the solvent is tert-amylalcohol.

In other embodiments, the reaction of the compound of formula (45) withthe compound of formula (63) or with the compound of formula (67) iscarried out in the presence of an iodide salt. In certain embodiments,the iodide salt is present in a sub-stoichiometric amount. In certainembodiments, the iodide salt is present in a catalytic amount. Theiodide salt is selected from the group consisting of NaI, KI, LiI, CsI,RuI, MgI₂, CaI₂, NH₄I, tetrabutylammonium iodide, and combinations oftwo or more thereof. In certain embodiments, the iodide salt is NaI.

The present disclosure also provides a composition comprising a compoundof formula (42)

and a transition metal catalyst, where R¹⁴ and R¹⁶ are eachindependently selected from —OH, —H, and —OR¹⁷; R¹⁵ is selected from—OH, —H, —OR¹⁷, ═O, and ═CH₂; and R¹⁷ is an oxygen protecting group.

In another embodiment, the present disclosure also provides acomposition prepared by admixing a compound of formula (42)

and a transition metal catalyst, where R¹⁴ and R¹⁶ are eachindependently selected from —OH, —H, and —OR¹⁷; R¹⁵ is selected from—OH, —H, —OR¹⁷, ═O, and ═CH₂; and R¹⁷ is an oxygen protecting group.

In other embodiments, the present disclosure also provides for acompound prepared by any method of the disclosure.

4. DETAILED DESCRIPTION

The present disclosure provides processes for the preparation of N-allylcompounds from tertiary amines. The disclosed processes involveN-dealkylation of the tertiary amine to provide an N-allyl carbamateintermediate that, in turn, is decarboxylated in a transitionmetal-catalyzed reaction to provide an N-allyl product. The tertiaryamines used as substrates in the presently disclosed reactions, methods,and processes also include compounds comprising the structural elementsof compounds of formula (2) including, without limitation, opioidcompounds.

Therefore, for example, in particular embodiments the present disclosureprovides methods for the conversion of oxymorphone to naloxone, andprocesses for the conversion of oripavine to naloxone that comprise thetransition metal-catalyzed reactions disclosed herein. In certainembodiments, the present disclosure provides “one pot” processes for theconversion of oxymorphone to naloxone, and “one pot” processes for theconversion of oripavine to naloxone that comprise the transitionmetal-catalyzed reactions disclosed herein.

In particular embodiments, the present disclosure provides methods forthe conversion of oxymorphone to naltrexone, and processes for theconversion of oripavine to naltrexone that comprise the transitionmetal-catalyzed reactions disclosed herein. In certain embodiments, thepresent disclosure provides “one pot” processes for the conversion ofoxymorphone to naltrexone, and “one pot” processes for the conversion oforipavine to naltrexone that comprise the transition metal-catalyzedreactions disclosed herein.

In further embodiments, the present disclosure provides methods for theconversion of oxymorphone to noroxymorphone, and processes for theconversion of oripavine to noroxymorphone that comprise the transitionmetal-catalyzed reactions disclosed herein. In certain embodiments, thepresent disclosure provides “one pot” processes for the conversion ofoxymorphone to noroxymorphone, and “one pot” processes for theconversion of oripavine to noroxymorphone that comprise the transitionmetal-catalyzed reactions disclosed herein.

In a further embodiment, the present disclosure provides methods for theconversion of naloxone to noroxymorphone.

In other embodiments, the present disclosure provides for a compoundprepared by any method of the disclosure.

4.1 Definitions

As used herein, the following terms are intended to have the followingmeanings:

“—(C₁-C₆) alkyl” as used herein means a straight or branched hydrocarbonchain having 1, 2, 3, 4, 5, or 6 carbon atoms that can contain orconsist of a carbocyclic group. Representative straight chain —(C₁-C₆)alkyls include methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and-n-hexyl. Representative branched chain —(C₁-C₆) alkyls include-iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, methylcyclopropyl, methyl cyclobutyl, and the like.

“—(C₂-C₆) alkyl” as used herein means a straight or branched hydrocarbonchain having 2, 3, 4, 5, or 6 carbon atoms that can contain a cycliccarbocyclic group. Representative straight chain —(C₂-C₆) alkyls include-ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl. Representativebranched chain —(C₂-C₆) alkyls include -iso-propyl, -sec-butyl,-iso-butyl, -tert-butyl, -iso-pentyl, -neopentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, methyl cyclopropyl, methylcyclobutyl, and the like.

“—(C₁-C₄) alkyl” as used herein means a straight or branched hydrocarbonchain having 1, 2, 3, or 4 carbon atoms that can contain a cycliccarbocyclic group. Representative straight chain —(C₁-C₄) alkyls includemethyl, -ethyl, -n-propyl, and -n-butyl. Representative branched chain—(C₁-C₄) alkyls include -iso-propyl, -sec-butyl, -iso-butyl,-tert-butyl, methyl cyclopentyl, and the like.

“—(C₂-C₆) alkenyl” as used herein means a straight chain or branchedhydrocarbon that can contain a cyclic carbocyclic group, having 2, 3, 4,5, or 6 carbon atoms and including at least one carbon-carbon doublebond. Representative straight chain and branched —(C₂-C₆) alkenylsinclude -vinyl, -allyl, -1-butenyl, -2-butenyl, -iso-butylenyl,-1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl,-2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, 3-hexenyl, and the like.

“—(C₂-C₆) alkynyl” as used herein means a straight chain or branchednon-cyclic hydrocarbon having 2, 3, 4, 5, or 6 carbon atoms andincluding at least one carbon-carbon triple bond. Representativestraight chain and branched —(C₂-C₆) alkynyls include -acetylenyl,-propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl,-3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl,and the like.

“Carbocyclic” as used herein means a ring structure in which all of thering atoms are carbon. A carbocyclic group can be saturated orunsaturated. An unsaturated carbocyclic group can contain 1, 2, 3, or 4double bonds or 1, 2, 3, or 4 triple bonds. Representative carbocyclicgroups include cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.

“Aryl” as used herein means a C₆-C₁₄ mono- or polycyclic aromatic ringsystem. Exemplary aryl groups include but are not limited to phenyl,naphthyl, anthryl, phenanthryl, and biphenyl groups.

“-(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo” asused herein means a 3-, 4-, 5-, 6-, or 7-membered monocyclicheterocyclic ring which is either saturated, unsaturated non-heteroaryl,or heteroaryl. A 3-membered heterocycle contains 1 heteroatom, a4-membered heterocycle can contain 1 or 2 heteroatoms, a 5-memberedheterocycle can contain 1, 2, 3, or 4 heteroatoms, a 6-memberedheterocycle can contain 1, 2, 3, or 4 heteroatoms, and a 7-memberedheterocycle can contain 1, 2, 3, 4, or 5 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The -(3- to7-membered)heterocycle can be attached via a nitrogen or carbon atom.Representative -(3- to 7-membered)heterocycles include pyridyl, furyl,thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl,thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl,piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl,hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like.

“Heteroaryl” as used herein encompasses aromatic heterocycle rings thatare -(5- to 10-membered)heteroaryl or -(5- or 6-membered)heteroaryl.

“-(5- to 10-membered)heteroaryl” as used herein means an aromaticheterocycle ring of 5, 6, 7, 8, 9, or 10 members, including both mono-and bicyclic ring systems, where at least one carbon atom of one or bothof the rings is replaced with a heteroatom independently selected fromnitrogen, oxygen, and sulfur, or at least two carbon atoms of one orboth of the rings are replaced with a heteroatom independently selectedfrom nitrogen, oxygen, and sulfur. In one embodiment, one of the -(5- to10-membered)heteroaryl's rings contain at least one carbon atom. Inanother embodiment, both of the -(5- to 10-membered)heteroaryl's ringscontain at least one carbon atom. Representative -(5- to10-membered)heteroaryls include pyridyl, furyl, benzofuranyl,thiophenyl, benzothiophenyl, quinolinyl, isoquinolinyl, pyrrolyl,indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl, thiadiazolyl, triazinyl,thienyl, cinnolinyl, phthalazinyl, and quinazolinyl.

“-(5- or 6-membered)heteroaryl” as used herein means a monocyclicaromatic heterocycle ring of 5 or 6 members where at least one carbonatom is replaced with a heteroatom independently selected from nitrogen,oxygen, and sulfur. In one embodiment, one of the -(5- or6-membered)heteroaryl's ring contains at least one carbon atom.Representative -(5- or 6-membered)heteroaryls include pyridyl, furyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl,pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,5-triazinyl, and thiophenyl.

“Halogen” as used herein means —F, —Cl, —Br, or —I. In certainembodiments, only a subset of the halogens are employed, e.g., thehalogen can be selected from —Cl, —Br, and —I.

“Leaving group” as used herein means an atom, a group of atoms, or amolecular fragment that is detached, eliminated, or removed from therest of a molecule during a reaction, e.g., a group that is displaced ina substitution reaction or elimination reaction. Representative,non-limiting examples of such leaving groups include —Cl, —Br, —I,—OS(O)₂C₄F₉, —OS(O)₂CF₃, —OS(O)₂F, -para-toluene sulfonate, and—OS(O)₂CH₃. In certain embodiments, the leaving group is a halogenselected from —Cl, —Br, and —I. In other embodiments, the leaving groupis —Br.

“Oxygen protecting group” as used herein means an atom, a group ofatoms, or a molecular fragment group introduced onto a molecule bychemical modification that is capable of modifying the reactivity of anoxygen atom, particularly that of a hydroxyl group, in order to obtainchemoselectivity in a subsequent chemical reaction and which, after thereaction for which protection is employed, can be removed withoutdisturbing the remainder of the molecule. Representative, non-limitingexamples of such oxygen protecting groups include allyl, acetyl,benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl,para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl,trityl, silyl (trimethylsilyl, tert-butyldimethylsilyl,tert-butyldimethylsilyloxymethyl, and tri-iso-propylsilyl), methyl, andethoxyethyl. In certain embodiments, an oxygen atom can be protectedduring a chemical reaction; e.g., the 3-hydroxyl of an opioid can reactwith a haloformate reagent to provide a “protected” 3-carbonatederivative. As used herein, alkylated hydroxyl groups are consideredprotected by the bound alkyl moiety; e.g., the 3-methoxy group ofthebaine is considered, in this context, to carry a 3-hydroxyl moietyprotected by the bound methyl group. In a similar manner, hydroxylgroups that react with a haloformate reagent yielding a carbonatederivative are considered protected hydroxyl groups. For example,reaction of a hydroxyl group with allyl chloroformate provides acarbonate moiety as the product, (—OC(O)O—CH₂—CH═CH₂), which can berepresented herein as —OR¹⁷, where the protecting group (“R′⁷”) is theallyl oxycarbonyl moiety (—C(O)O—CH₂—CH═CH₂).

In connection with the heterocyclic or heteroaryl ring of formula (5)being a subunit of a polycyclic ring system comprising any combinationof 1, 2, 3, 4, 5, or 6 carbocyclic, heterocyclic, aryl, or heteroarylrings, each of which is unsubstituted or substituted with 1, 2, 3, 4, or5 independently-selected R⁵² groups, the following polycyclic ringsystems are non-limiting examples of a heterocyclic ring of formula (5)being a subunit of a polycyclic ring system comprising a combination of5 total carbocyclic, heterocyclic, and aryl rings, each of which isunsubstituted:

The following polycyclic ring systems are non-limiting examples of aheterocyclic ring of formula (5) being a subunit of a polycyclic ringsystem comprising a combination of 6 total carbocyclic, heterocyclic,and aryl rings, each of which is unsubstituted:

The following polycyclic ring system is a non-limiting example of aheterocyclic ring of formula (5) being a subunit of a polycyclic ringsystem comprising a combination of 4 total rings, one each of acarbocyclic, heterocyclic, aryl, and heteroaryl ring, each of which isunsubstituted:

When a first group is “substituted with one or more” second groups, eachof one or more of the first group's hydrogen atoms is replaced with anindependently-selected second group. In one embodiment, a first group issubstituted with 1, 2, or 3 independently-selected second groups. Inanother embodiment, a first group is substituted with 1 or 2independently-selected second groups. In another embodiment, a firstgroup is substituted with only one second group.

“Transition metal catalyst” as used herein means a catalyst comprisingany of the transition elements capable of participating in a catalyticcycle, i.e., any of the metallic elements within Groups 3 to 12 in thePeriodic Table. As used herein, the phrase “transition metal catalyst”encompasses those catalysts that comprise a transition metal of variousoxidative states and that are capable of allylic decarboxylation. Incertain embodiments, transition metal catalysts useful in the methodsdisclosed herein include complexes comprising a transition metalselected from the group consisting of Pd[0], Pd[II], Ni[0], Ni[II],Mo[0], Ru[II], Rh[I], and combinations of two or more thereof. Incertain embodiments, transition metal catalysts useful in the methodsdisclosed herein include those comprising 1, 2, 3, or 4 phosphinemoieties. Non-limiting examples of such transition metal complexesinclude Pd(PPh₃)₄, Pd(Ph₂P(CH₂)₄PPh₂)₂, Ni(PPh₃)₄, Ni(Ph₂P(CH₂)₄PPh₂)₂,((pentamethylcyclopentadienyl)RuCl)₄, [Pd(DBA)₂]/PPh₃, [Pd(OAc)₂]/PPh₃,[Ni(COD)₂]/PPh₃, NiCl₂/PPh₃, Ni[P(OEt)₃]4, [Mo(CO)₆-DPPE],RhH(PPh₃)₄—P(n-Bu)₃, and combinations of two or more thereof. In certainembodiments, the transition metal catalyst comprises Pd(PPh₃)₄. Incertain embodiments, the transition metal catalyst consists essentiallyof Pd(PPh₃)₄. In certain embodiments, the transition metal catalyst isPd(PPh₃)₄. In certain embodiments, the transition metal catalyst can beprepared in situ. For example, triphenylphosphine (PPh₃) can be added toa mixture containing PdCl₂ to prepare the catalysts PdCl₂(PPh₃)₂ orPd(PPh₃)₄ in situ.

“Tertiary alcohol” as used herein refers to an alcohol of formula (4)

in which R⁶, R⁷, and R⁸ are each independently —(C₁-C₆)alkyl.Illustrative tertiary alcohols therefore include tert-amyl alcohol,tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol,3-ethyl pentanol, 3-ethyl-3-pentanol, and 2-methyl-2-hexanol, andcombinations of two or more thereof.

“Zinc-containing reagent” as used herein refers to any zinc-containingreagent capable to perform the reactions for which it is used in thecontext of present disclosure. In certain embodiments, thezinc-containing reagent can be selected from the group consisting ofdiethyl zinc, elementary zinc—e.g., in the form of zinc dust-,zinc-copper couple, and combinations thereof. In certain embodiments,the zinc has the oxidation number 0 (Zn[0]).

An “allyl haloformate equivalent,” is a compound from which an allylhaloformate can readily be formed, e.g., a compound selected from amongsuch compounds as formulae (6), (8), (13), (23), and (46), according tothe methods disclosed herein, e.g., as depicted in Schemes 11, 12, and29.

An “allyl scavenger” as used herein can be selected from those known inthe art, e.g., from among the following illustrative examples:

and combinations of two or more thereof. In another embodimentillustrative example, the allyl scavenger can is be selected from thegroup consisting of sodium 2-ethylhexonate, morpholine, dimedone,4-methylbenzensulfinic acid, sodium hydroxymethyl sulfinate,benzenesulfinic acid, sodium toluene sulfinate, sodium 2-thiophenesulfinate, tetrabutylammonium toluene sulfinate, N,N-dimethyl barbituricacid, sodium 4-chloro-3-nitrobenzene sulfinate, formic acid, diethylamine, methanol, ethanol, and combinations of two or more thereof. In afurther illustrative example, the allyl scavenger is compound (146)

In a further illustrative example, the allyl scavenger is methanol. A“hydrogenation” is the addition of two hydrogen atoms to a double bond,thus converting it into a single bond, or the addition of two or fourhydrogen atoms to a triple bond, thus converting it into a double or asingle bond. It can be carried out using routine methods known in theart, for example, with a hydrogen atmosphere in the presence of aprecious metal catalyst such as a carbon-supported palladium (Pd/C) orPt/C. In other embodiments, a double bond can be subjected to transferhydrogenation. In certain embodiments, reduction (hydrogenation) of analkyne to an alkene is carried out in methanol with hydrogen andquinoline in the presence of 5% Lindlar catalyst. In other embodiments,the reduction of an alkyne to an alkene is carried out in the presenceof NaBH₄, hydrogen, diethyl amine and Ni[II]acetate in aqueous methanol.

An “oxidation” is the addition of one or more (generally two) oxygenatoms to an unsaturated structural element. It can be carried out usingroutine methods known in the art. In certain embodiments, it is carriedout using a peroxy acid, wherein the peroxy acid can be peroxybenzoicacid, performic acid, or peracetic acid, which can be prepared in situby mixing hydrogen peroxide and excess formic acid or excess aceticacid. In a particular embodiment, it is performic acid, prepared bycombining formic acid and hydrogen peroxide in a reaction mixture. Incertain embodiments, the oxidation is carried out by adding osmiumtetroxide and N-methyl morpholine N-oxide.

Numbering of the atoms in the structures disclosed herein is based uponthe following scheme, using the chemical structure of morphine as thereference:

“Sub-stoichiometric amount” means an amount which is smaller than thestoichiometric amounts of a reactant(s) of the reactions describedherein. For example, a sub-stoichiometric amount of the iodide salt usedas catalyst in some embodiments is less than 100 mol % of the structureof formula (2). A sub-stoichiometric amount can be any numerical valuewithin the range of from 0.001 to 99 mol % of the starting reactant(e.g., compound (2) or compound (3)) or the compounds taking place inthe reaction schemes described herein. In certain embodiments, thesub-stoichiometric amount is in the range of from 20 to 70 mol %, 25 to65 mol % or 30 to 60 mol % of the starting reactant, e.g., 30 mol % or60 mol %.

“Catalytic amount” is a sub-stoichiometric amount which is sufficient toexert a catalytic effect on the reactions described herein. Typically, acatalytic amount can be any numerical value within the range of from0.01 to 99 mol % of the starting reactant (e.g., compound (2) orcompound (3)) or the compounds taking its place in the reaction schemesdescribed herein. In certain embodiments, the catalytic amount is in therange of from 20 to 70 mol %, 25 to 65 mol % or 30 to 60 mol % of thestarting reactant or has any numerical value within these ranges, e.g.,30 mol % or 60 mol %. An illustrative example for a catalytic compoundto which these ranges apply is the iodide salt used in the context ofpresent disclosure. In certain other embodiments, the catalytic amountis in the range of from 0.001 to 30 mol %, 0.01 to 20 mol %, 0.1 to 10mol %, 2 to 8 mol %, or 3 to 7 mol % of the starting reagent or has anynumerical value within these ranges, e.g., about 5 mol %. Anillustrative example for a compound to which these ranges apply is thetransition metal catalyst used in the context of present disclosure.

“Consisting essentially of” in certain embodiments of present disclosuremeans that the subsequently named component(s) is necessarily includedbut that another unlisted ingredient(s) that does not materially affectthe basic and novel properties can also be present. In certainembodiments, the subsequently named component is the major component ofthe compound named before the term, e.g., a solvent consistingessentially of a tertiary alcohol (i.e., a compound of formula (5))contains said tertiary alcohol (or said mixture of tertiary alcohols,see above) as major component, typically in an amount of more than 50vol %, and other solvents (e.g., 1,2-dichloroethane, chloroform,dichloromethane, or acetonitrile) in a total amount of less than 50 vol%. In these embodiments, “consisting essentially of” means “comprisingbetween 50 vol % and 100 vol % or any numeric value within this range ofthe subsequently named compound.” In certain embodiments, “consistingessentially of” means “comprising from 80 to up to 100 vol % (excepting100 vol %, as this is represented by “consisting of” in the context ofpresent disclosure) or any numeric value within this range of thesubsequently named compound, e.g., as in “a solvent comprising from 80to up to 100 vol % tertiary alcohol”.

Compounds disclosed herein can contain one or more asymmetric centersand can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. In reference to compounds of formula (1) forexample, as well as all other compounds described herein that containone or more olefinic double bonds or other centers of geometricasymmetry, unless specified otherwise, it is intended to include both Eand Z geometric isomers. The method disclosed herein can be used witheach of the enantiomers, diastereomers, and other stereoisomeric formsof the reagents disclosed herein to provide each of the enantiomers,diastereomers, and other stereoisomeric forms of the products disclosedherein.

In the event of doubt as to the agreement of a depicted chemicalstructure and a chemical name, the depicted chemical structure governs.

It will be appreciated that various features of the disclosure whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment unless otherwisespecifically herein excluded. Conversely, various features of thedisclosure which are, for brevity, described in the context of a singleembodiment, can also be provided separately and/or in any suitablesubcombination unless otherwise specifically herein excluded.

4.2 Methods for Making N-Allyl Compounds from Tertiary Amines

The present disclosure provides a two-step process for formation ofN-allyl compounds from tertiary amines, which is depicted in Scheme 1,where R¹ through R⁷ are as defined above.

The first step involves N-dealkylation of a tertiary amine of formula(2) to provide an N-allyl carbamate intermediate of formula (3) that isdecarboxylated in the second step in a transition metal-catalyzedreaction to provide the N-allyl product, a compound of formula (1).

The present disclosure also provides a set of alternative reagents andmethods, which can comprise one or more reactions that are useful forconverting a tertiary amine of formula (2) to the N-allyl carbamateintermediate of formula (3).

For example, in one embodiment, the tertiary amine is contacted with anallyl haloformate, e.g., a compound of formula (93)

to provide the allyl carbamate product of formula (3) directly. Inanother embodiment, the tertiary amine is contacted with a haloformatereagent to provide a carbamate compound (e.g., a compound of formula (7)or a compound of formula (9)) that is subsequently converted to thecorresponding N-allyl carbamate intermediate of formula (3).

For example, in another embodiment, the tertiary amine of formula (2) iscontacted with a haloformate reagent carrying at least one leaving group(e.g., a compound of formula (6) or a compound of formula (8)), toprovide a carbamate derivative (e.g., a compound of formula (7) or acompound of formula (9)). In certain embodiments, the haloformatereagent comprises one leaving group. In certain embodiments, thehaloformate reagent comprises two leaving groups. The carbamatederivative is converted to the corresponding N-allyl carbamate and thento the N-allyl product in sequential transition metal-catalyzedreactions.

The two steps of Scheme 1 are illustrated by the reaction schemes below,in which oxymorphone and oxycodone are (1) demethylated to thecorresponding carbamate derivatives and (2) decarboxylated to thecorresponding N-allyl compounds.

4.2.1 Dealkylation of Tertiary Amines and Formation of CarbamateIntermediates: Conversion of Oxymorphone to N-Allyl Noroxomorphone andOxycodone to N-Allyl Noroxycodone

As noted above, the process disclosed herein for conversion of tertiaryamines to N-allyl derivatives thereof can be depicted as comprising twosteps. In the first step, which is depicted in Scheme 2, a tertiaryamine is demethylated by contacting the tertiary amine with an allylhaloformate (in this case allyl chloroformate, compound (102)) in asolvent in the presence of a base to provide the intermediate N-allylcarbamate.

As previously discussed, e.g., in connection with R^(14′) and R^(16′),the definitions of R⁴⁴ and R⁴⁵ will depend on the functional groupspresent at R⁴² and R⁴³, respectively. It will be appreciated that whenR⁴² is H, then —OR⁴⁴ can include allyl carbonate

Likewise, when R⁴³ is H, then —OR⁴⁵ can be an allyl carbonate. Theextent of allyl carbonate formation at the positions comprising R⁴² andR⁴³ is dependent on the relative rate of reaction at these sitescompared to the rate of reaction of the tertiary amine. Allyl carbonatescan be converted back to —OH groups using methods described below. Itwill be further appreciated that when —OR⁴² is selected to be aparticular moiety that is not an —OH group, then —OR⁴⁴ is also thatparticular —OR⁴² moiety. Likewise, it will be appreciated that when—OR⁴³ is selected to be a particular moiety that is not an —OH group,then —OR⁴⁵ is also that particular —OR⁴³ moiety.

Table 1 summarizes data from five reactions according to Scheme 2. Theseinclude N-demethylation of: 3,14-bis-acetoxy-oxymorphone (Reaction 1 inTable 1), oxycodone (Reaction 2), oxymorphone (Reaction 3), and 3-allyloxymorphone (Reaction 4). Each of Reactions 1-4 was carried out withexcess (at least 6 equivalents excess) allyl chloroformate (compound(102)) in the presence of potassium carbonate (1.5 equivalents) in1,2-dichloroethane at reflux temperature for 48 hours. In the first fourreactions, which were carried out at the reflux temperature of1,2-dichloroethane (approximately 84° C.), 50-78% of the starting opioidwas consumed.

In Reaction 5, oxymorphone was demethylated with excess allylchloroformate (compound (102)) in the presence of K₂CO₃ using tert-amylalcohol as the solvent. Reaction 5 was carried out according to themethod described in Example 3 (described below), in which additionalamounts of allyl chloroformate are added throughout the duration of thereaction. In this instance, more than 97% of oxymorphone was consumed.

TABLE 1 % Starting Opioid Reaction R⁴² R⁴³ Solvent Consumed 1 AcetylAcetyl ClCH₂CH₂Cl 60 2 CH₃ H ClCH₂CH₂Cl 78 3 H H ClCH₂CH₂Cl 62 4 Allyl HClCH₂CH₂Cl 50 5 H H

>97

4.2.2 Transition Metal-Catalyzed Decarboxylation of N-Methyl Opioids toProvide N-Allyl Products

In the second step of Scheme 2, the intermediate N-allyl carbamate isdecarboxylated in a transition metal-catalyzed reaction to provide thecorresponding N-allyl derivative. As illustrated in Scheme 3, thecarbamate products of Table 1 were contacted with a transition metalcatalyst comprising palladium[0] in the reaction depicted in Scheme 3.

As previously discussed, e.g., in connection with R^(14′) and R^(16′),the definitions of R⁴⁶ and R⁴⁷ will depend on the functional groupspresent at R⁴⁴ and R⁴⁵, respectively. In Scheme 3, R⁴⁶ and R⁴⁷ can be—H, —CH₃, acetyl, or allyl.

Table 2 provides the results obtained upon decarboxylation of theoxymorphone and oxycodone functionalized carbamate starting compoundsidentified in Table 2. As indicated in Table 2, in certain embodimentsreactions with 3,14-bis-acetoxy compounds provided a complex mixture ofproducts (Reaction 1 of Table 2 below). In contrast, decarboxylation ofsubstrates in which the 3- and 14-hydroxyl groups were not protected byacetylation, and therefore were present as free hydroxyl groups or ascarbonate derivatives thereof, provided improved yields (Reactions 2 and3 of Table 2). In these embodiments, the decarboxylation reactions werecarried out in dichloromethane at a temperature of about 25° C. in thepresence of a catalytic amount (0.05 equivalents) oftetrakis(triphenylphosphine)palladium[0]. In certain embodiments, R⁴⁷ is—H.

TABLE 2 Reaction R⁴⁴ R⁴⁵ Conversion 1 Acetyl Acetyl About 5%, manyproducts 2 CH₃ H/Allyl carbonate ^((a)) >99% 3 Allyl carbonate ^((b))H/Allyl carbonate ^((a)) >99% ^((a)) Indicates a mixture of 14-hydroxyland 14-allyl carbonate species. ^((b)) Indicates that the 3-position ofthe compound carried an allyl carbonate moiety. As noted below, as inReaction 3 of Table 2, the 3-carbonate moiety is converted to the3-allyl ether in the transition metal-catalyzed decarboxylationreactions depicted in Scheme 3 (i.e., R⁴⁶ is allyl).

It has also been found that 14-functionalized allyl carbonatesselectively undergo allylic decarboxylation, yielding the desired14-hydroxyl products. Therefore, in Reactions 2 and 3 of Table 2, theproduct of the transition metal-catalyzed reaction depicted in Scheme 3is one in which R⁴⁷ is —H.

It has also been found that allylic decarboxylation was successful with3-allyl functionalized substrates, e.g., where R⁴⁴ of Scheme 3 is anallyl carbonate moiety (Reaction 3 of Table 2). In this instance, the3-allylcarbonate group was converted to a 3-allyl ether derivativerather than to a free hydroxyl (i.e., R⁴⁶ is allyl). The 3-allyl ethercan be converted to the corresponding 3-OH in a transitionmetal-catalyzed reaction in the presence of a base and an allylscavenger (e.g., methanol), as depicted in Scheme 4.

In other embodiments, e.g., as depicted in Scheme 10, formation of the3-allyl ether can be avoided by incorporating a base-treatment stepafter synthesis of the N-allyl carbamate derivative comprising a3-carbonate moiety but before the transition metal-catalyzeddecarboxylation reaction depicted in Scheme 3 above and Scheme 5 below.

4.3 Processes for Conversion of Oxymorphone to Naloxone and forConversion of Oripavine to Naloxone 4.3.1 Process for the Conversion ofOxymorphone to Naloxone

As indicated in Section 4.2.1, a tertiary amine, e.g., oxymorphone, canbe contacted with allyl chloroformate to provide the 17-carbamatederivative, e.g., the 17-carbamate of of oxymorphone,17-allyloxycarbonyl-noroxomorphone (compound (105)) (e.g., see Example 3below). Compound (105) in turn can be decarboxylated to provide compound(104) (naloxone) in a transition metal-catalyzed reaction, as depictedin Scheme 5.

In another illustrative embodiment, the decarboxylation reactiondepicted in Scheme 5 can be incorporated in an overall process, depictedin Scheme 6, for conversion of oripavine to naloxone. In fact, thesynthetic approach of Scheme 6 can be carried out as a “one pot” processwithout chromatographic isolation of the intermediate products.

4.3.2 Process for Synthesis of Naloxone from Oripavine

The transition metal-catalyzed decarboxylation of 17-allyloxycarbonylnoroxymorphone can be exploited to provide the overall process forconversion of the natural product oripavine (compound (106)) to thesemi-synthetic derivative thereof, naloxone (compound (104)) accordingthe reaction scheme depicted below. In these reactions, the 3-hydroxylof oripavine and the 3- and 14-hydroxyls of compound (107) and compound(108) (oxymorphone) need not be protected in one or more separate steps.As disclosed below, the phenolic 3-OH is expected to react with theallyl haloformate reagent employed in the demethylation reaction toyield the 3-allyl carbonate. Although the 14-OH is typically lessreactive than the 3-OH group, a 14-allyl carbonate group can also beformed by reaction with the haloformate reagent.

Step 1 of Scheme 6 depicts the oxidation of oripavine (compound (106))to 14-hydroxymorphinone (compound (107)) which can be carried out bycontacting oripavine with a peroxyacid such as peracetic acid, performicacid, or m-chloroperbenzoic acid. The peroxy acid can be formed in situ,for example by addition of hydrogen peroxide to acetic acid or to formicacid.

In Step 2 of Scheme 6, the oxidized compound (compound (107)) ishydrogenated to oxymorphone (compound (108)). Hydrogenation can becarried out, for example, with a hydrogen atmosphere in the presence ofa precious metal catalyst such as a carbon-supported palladium (Pd/C) orPt/C (see, e.g., Krassnig et al. (1996) Arch. Pharm. Med. Chem.329:325-326; U.S. Pat. No. 5,112,975 to Wallace; U.S. Pat. No. 4,472,253to Schwartz; and U.S. Pat. Nos. 1,485,673 and 1,468,805 to Freund etal., each of which is hereby incorporated by reference in its entirety).In other embodiments, the 7,8-double bond of compound (107) can besubjected to transfer hydrogenation to provide compound (108) (see,e.g., WO 2005/097801 A1; U.S. Pat. No. 6,177,567 B1; WO 2006/094672 A1;and Fahrenholtz (1972) J. Org. Chem. 37(13):2204-2207, each of which ishereby incorporated by reference in its entirety).

In Step 3 of Scheme 6, oxymorphone can be contacted with an allylhaloformate, e.g., allyl chloroformate

(compound (102)), in a solvent in the presence of a base to provide thecorresponding allyl carbamate, a compound of formula (70)

in which R⁴⁸ is —OC(O)OCH₂CH═CH₂ and R⁴⁹ is —OH or —OC(O)OCH₂CH═CH₂.

In one embodiment, the Step 3 starting material, e.g., oxymorphone(compound (106)), is taken up in a solvent in the presence of a base.The solvent can be any suitable solvent in which the reaction canproceed. In certain embodiments, the solvent is selected from the groupconsisting of ether solvents, acetonitrile, benzene, DMF, DMSO,N,N-dimethylpropionamide, DMPU, DMI, DME, DMAC, NMP, ethyl acetate,ethyl formate, ethyl-methyl ketone, iso-butylmethylketone, formamide,hexamethylphosphoramide, methyl acetate, N-methylacetamide,N-methylformamide, nitrobenzene, nitromethane, propionitrile, sulfolane,tetramethylurea, THF, toluene, CHCl₃, CH₂Cl₂, 1,2-dichloroethane, THF,acetone, tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol,2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol,acetonitrile, benzene, carbon tetrachloride, chlorobenzene,1,2-dichlorobenzene, DMF, trifluorotoluene, 1,4-dioxane,1,2-dimethoyxethane, xylene, and combinations of two or more thereof.

In particular embodiments of Step 3, the solvent comprises, consistsessentially, or is (i.e., consists of) a tertiary alcohol selected fromthe group consisting of tert-amyl alcohol, tert-butyl alcohol,3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol,2-methyl-2-hexanol, and combinations of two or more thereof. In aspecific embodiment, the solvent comprises tert-amyl alcohol. In anotherspecific embodiment, the solvent consists essentially of tert-amylalcohol. In another specific embodiment, the solvent is tert-amylalcohol.

In certain embodiments of Step 3, the base is selected from the groupconsisting of borate salts (such as, for example, NaBO₃), di- andtri-basic phosphate salts (such as, for example, Na₂HPO₄, Na₃PO₄,combinations thereof, and the like), bicarbonate salts (such as, forexample, NaHCO₃, KHCO₃, combinations thereof, and the like), hydroxidesalts (such as, for example, NaOH, KOH, combinations thereof, and thelike), carbonate salts (such as, for example, Na₂CO₃, K₂CO₃, Cs₂CO₃,combinations of two or more thereof, and the like), organic protonacceptors (such as, for example, pyridine, triethylamine,di-iso-propylethylamine, N-methylmorpholine, N,N-dimethylaminopyridine,combinations of two or more thereof, and the like), organic buffers(such as, for example, N-(2-acetamido)-2-aminoethane sulfonic acid(ACES), N-(2-acetamido)-iminodiacetic acid (ADA),N,N-bis(2-hydroxyethyl)glycine (BICINE),3-(cyclohexylamino)-1-propanesulfonic acid (CAPS), 2-(cyclohexylamino)ethanesulfonic acid (CHES),4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS),4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES),2-(4-morpholinyl) ethanesulfonic acid (MES), 4-morpholinepropanesulfonicacid (MOPS), 1,4-piperazinediethanesulfonic acid (PIPES),[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid(TAPS), 2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonicacid (TES), any salt thereof and/or combinations of two or more thereof,and the like. In certain embodiments, the base is selected from thegroup consisting of NaHCO₃, KHCO₃, LiHCO₃, KHCO₃, LiHCO₃, Na₂CO₃, K₂CO₃,Cs₂CO₃, NaOH, KOH, Na₂HPO₄Na₃PO₄, K₂HPO₄, K₃PO₄, and combinations of twoor more thereof. In specific embodiments, the base is selected from thegroup consisting of triethylamine, di-iso-propylethylamine, Na₂CO₃,NaHCO₃, KHCO₃, K₂CO₃, Cs₂CO₃, and combinations of two or more thereof.In a specific embodiment, the base is NaHCO₃.

In one embodiment, Step 3 of Scheme 6 can be carried out in the presenceof an iodide salt, which can be selected from the group consisting ofNaI, KI, LiI, CsI, RuI, MgI₂, CaI₂, NH₄I, tetrabutylammonium iodide, andcombinations of two or more thereof. In certain embodiments, the iodidesalt is NaI. In certain embodiments, the iodide salt is present in asub-stoichiometric amount. In certain embodiments, the iodide salt ispresent in a catalytic amount.

In one embodiment, the allyl haloformate (compound (48)), here allylchloroformate (compound (102)), is added to the mixture and the reactionrun at a temperature within the range of from about 15° C. to about 85°C., or from about 20° C. to about 75° C., or from about 25° C. to about75° C., or from about 35° C. to about 70° C., or from about 45° C. toabout 65° C., or from about 50° C. to about 60° C. for an initial periodof time within the range of from about 0.5 hours to about 2 hours, orfrom about 0.5 hours to about 1.5 hours, or from about 0.75 hours toabout 1.25 hours. In certain embodiments, the reaction is run at atemperature of about 55° C. In certain embodiments, the reaction is runfor an initial period of about one hour. An aliquot of the mixture isanalyzed to determine the extent of the reaction. If the reaction hasnot proceeded to the extent desired, the mixture is heated, therebyremoving water (e.g., as an azeotrope with tert-amyl alcohol) and allylchloroformate, as well as any ethanol, allyl chloride, or allyl alcoholthat might be present in the reaction. After cooling, the solvent isreplenished as necessary, additional allyl haloformate reagent is added,and the reaction continued. This cycle of testing, distillation, solventreplenishment, and allyl haloformate addition can be repeated one ormore times. In certain embodiments, particularly where the basetreatment step (Step 4A of Scheme 10 below) is omitted, the allylcarbamate product (e.g., see the compound of formula (70)) R⁴⁸ moietycan be an allyloxycarbonyl moiety and, in certain embodiments, R⁴⁹ willbe a hydroxyl moiety (e.g., see compound (109)) while, in otherembodiments, R⁴⁸ and R⁴⁹ will both be allyloxycarbonyl moieties (e.g.,see compound (110)). Where R⁴⁸ and R⁴⁹ are each hydroxyl moieties, thecompound of formula (70) is 17-allyloxycarbonyl noroxymorphone, compound(105).

In certain embodiments, e.g., those in which R⁴⁸ and/or R⁴⁹ areallyloxycarbonyl groups, Step 4 can involve multiple sub-steps thatresult in conversion of the 17-allyloxycarbonyl intermediate, carrying a3-allyloxycarbonyl moiety and/or 14-allyloxycarbonyl moiety, to the endproduct, naloxone, as depicted in Scheme 6. Step 4 of Scheme 6,therefore, reflects conversion of the allyl carbamate group(17-allyloxycarbonyl group) of compound (70) to an N-allyl moiety viathe transition metal-catalyzed reaction depicted in Schemes 1 and 3, andwhere both R⁴⁸ and R⁴⁹ either are hydroxyl groups or are converted tohydroxyl groups, the product of Step 4 of Scheme 6 is compound (104),i.e., naloxone.

More specifically, the product of Step 3 of Scheme 6 (i.e., compounds offormula (70)) can include both of the following compounds.

That is, the product of Step 3 of Scheme 6 is expected to carry anallyloxycarbonyl group at both the 3-position and the 17-position, andcan also carry an allyloxycarbonyl moiety at the 14-position as well. Incertain embodiments, the product of Step 3 of Scheme 6 carries a freehydroxyl at the 14-position and, in particular embodiments, the productof Step 3 of Scheme 6 is almost entirely compound (109).

In certain embodiments, particularly at early time points (see, e.g.,Example 3), an initial product of Step 3 of Scheme 6, can be compound(145):

and therefore, the products of Step 3 of Scheme 6 can include compound(145), compound (109), and compound (110).

In one embodiment, the product(s) of Step 3 of Scheme 6 are contactedwith a transition metal catalyst, whereby the 14-allyloxycarbonyl groupis converted to a hydroxyl, the N-allylcarbamate group is converted toan N-allyl moiety, and the 3-allyloxycarbonyl is converted to a 3-allylether moiety, as depicted in Scheme 7.

In certain embodiments, the mixture of3,17-diallyloxycarbonyl-noroxymorphone (compound (109)) and3,14,17-triallyloxycarbonyl-noroxymorphone (compound (110)) is dissolvedin a solvent (e.g., chloroform or methylene chloride) and a suitabletransition metal catalyst, e.g.,tetrakis(triphenylphosphine)palladium[0], is added. The decarboxylationreaction is carried out for a suitable time and at an appropriatetemperature for the reaction to proceed to completion. In oneembodiment, the reaction is carried out for four hours at a temperatureof about 20° C.

The reaction mixture is filtered and the filtrate concentrated. Theresulting oil is taken up in a solvent, e.g., ethyl acetate, extractedwith acid, e.g., 0.5N HCl, and the aqueous layer washed with an organicsolvent, which in one embodiment is ethyl acetate. The aqueous layer isbasified, e.g., to pH 9.1 using 50% aqueous NaOH, and extracted with anorganic solvent which, in one embodiment, is chloroform. The recoveredorganic layers are combined, dried, filtered, and concentrated toprovide an oil comprising the product, 3-allyl-naloxone (compound(103)), as depicted in Scheme 7 above.

In one embodiment, the 3-allylether naloxone product (compound (103)) isoxygen de-allylated to naloxone, by contact with a suitable transitionmetal catalyst, e.g., tetrakis(triphenylphosphine)palladium[0], in thepresence of a base and an allyl scavenger. In certain embodiments, thebase is K₂CO₃.

In one embodiment, the allyl scavenger can be selected from the groupconsisting of sodium 2-ethylhexonate, morpholine, dimedone,4-methylbenzensulfinic acid, sodium hydroxymethyl sulfinate,benzenesulfinic acid, sodium toluene sulfinate, sodium 2-thiophenesulfinate, tetrabutylammonium toluene sulfinate, N,N-dimethyl barbituricacid, sodium 4-chloro-3-nitrobenzene sulfinate, formic acid, diethylamine, methanol, ethanol, and combinations of two or more thereof. Inanother embodiment, the allyl scavenger is methanol.

In a particular embodiment, the base is K₂CO₃ and the allyl scavenger ismethanol, i.e., the reaction is that depicted in Scheme 8.

Thus, in one embodiment, 3-allylether-naloxone is taken up in a suitablesolvent and contacted with a base and a transition metal catalyst in thepresence of an allyl scavenger. The base can be selected from amongthose described above as useful in Step 3 of Scheme 6, and thetransition metal catalyst is a catalyst that comprises a transitionmetal selected from the group consisting of Pd[0], Pd[II], Ni[0],Ni[II], Mo[0], Ru[II], Rh[I], and combinations of two or more thereof.In certain illustrative embodiments, the transition metal catalyst is acomplex selected from the group consisting of Pd(PPh₃)₄,Pd(Ph₂P(CH₂)₄PPh₂)₂, Ni(PPh₃)₄, Ni(Ph₂P(CH₂)₄PPh₂)₂,((pentamethylcyclopentadienyl)RuCl)₄, [Pd(DBA)₂]/PPh₃, [Pd(OAc)₂]/PPh₃,[Ni(COD)₂]/PPh₃, NiCl₂/PPh₃, Ni[P(OEt)₃]₄, [Mo(CO)₆-DPPE],RhH(PPh₃)₄—P(n-Bu)₃, and combinations of two or more thereof. In anotherembodiment, the transition metal catalyst comprises 1, 2, 3, or 4phosphine moieties. In another embodiment, the transition metal catalystis tetrakis(triphenylphosphine)palladium[0]. In one embodiment, the baseis potassium carbonate and the allyl scavenger is methanol. Thede-allylation reaction is carried out for a suitable time and at anappropriate temperature for the reaction to proceed to completion; inone embodiment, the reaction is carried out for four hours at atemperature of about 20° C., i.e., a temperature typically within therange of from about 15° C. to about 25° C., or from about 17° C. toabout 23° C., or from about 19° C. to about 21° C.

The reaction mixture is filtered and the filtrate concentrated. Theresulting oil is taken up in a solvent, e.g., ethyl acetate, extractedwith acid, e.g., 0.5N HCl, and the aqueous layer washed with an organicsolvent, which in one embodiment is ethyl acetate. The aqueous layer isbasified, e.g., to pH 9 using 50% aqueous NaOH, and extracted with anorganic solvent which, in one embodiment, is chloroform. The recoveredorganic layers are combined, dried, filtered, and concentrated toprovide an oil comprising the product, naloxone.

In certain embodiments, the reactions of Schemes 7 and 8 can be combinedby including a base and an allyl scavenger in the reaction mixture usedfor decarboxylative de-allylation, thereby providing the reaction schemedepicted in Scheme 9.

In certain embodiments, the transition metal catalyst is Pd(PPh₃)₄, thebase is K₂CO₃, the solvent is chloroform, and the allyl scavenger ismethanol. The reaction depicted in Scheme 9 therefore permits formationof naloxone from the 3,17-diallyloxycarbonyl and3,14,17-triallyloxycarbonyl intermediates, and combinations thereof, ina single step.

4.3.3 Additional Process for Making Naloxone from Oripavine

In another approach, the 3-allylcarbonate and 14-allylcarbonate groupscan be cleaved before the transition metal-catalyzed decarboxylation ofthe 17-carbamate moiety. In this embodiment, once Step 3 of Scheme 6 isdeemed complete, base and water are added and the reaction mixture isheated at a temperature and for a time sufficient to hydrolyze the3-allyoxycarbonyl and 14-allyloxycarbonyl moieties. After cooling, thereaction mixture is first acidified to a pH of about pH 1 to about pH 2,and the layers allowed to separate. The organic layer is retained,washed with 10% sodium hydrogen sulfate, and concentrated to provide17-allyloxycarbonyl-noroxymorphone. This hydrolysis step of can beincorporated into an overall process, e.g., for the production ofnaloxone from oripavine, as depicted in Scheme 10.

The base-mediated hydrolysis step described above is depicted as Step 4Ain Scheme 10 and the transition metal-catalyzed decarboxylation step(Step 4B of Scheme 10) corresponds to the reaction depicted in Schemes 3and 5, above.

In certain embodiments, the compounds of formula (109) and formula (110)are converted to compound (104) in Step 4C mediated by a transitionmetal catalyst in the presence of an allyl scavenger (e.g., as depictedin Scheme 9).

In one embodiment of the process of Scheme 10, oripavine (compound(106)) is oxidized (Step 1) with a peroxy acid to 14-hydroxy morphinone(compound (107)). In certain embodiments, the peroxy acid isperoxybenzoic acid, performic acid, or peracetic acid, which can beprepared in situ by mixing hydrogen peroxide and excess formic acid orexcess acetic acid. In a particular embodiment, oripavine is oxidized inperformic acid, prepared by combining oripavine, formic acid, andhydrogen peroxide into a reaction mixture. The reaction mixture iswarmed to a suitable temperature within the range of from about 25° C.to about 80° C., or from about 30° C. to about 70° C., or from about 35°C. to about 65° C., or from about 40° C. to about 60° C., or from about45° C. to about 55° C., and maintained at that temperature for about 0.5hours to about 3.5 hours, or from about 1 hour to about 3 hours, or fromabout 1.5 hours to about 2.5 hours, until the starting material isconsumed. In particular embodiments, the oxidation is carried out atabout 48° C. for about 2 hours.

The crude product, 14-hydroxy-morphinone (compound (107)) of theoxidation reaction (Step 1) is then taken directly on to the second stepwithout purification. Thus, once oxidation is complete, the crude14-hydroxy-morphinone (compound (107)) is hydrogenated (Step 2) in thepresence of a palladium catalyst under a hydrogen atmosphere at 40-45°C. (Step 2) to provide oxymorphone (compound (108)). The hydrogen can beprovided at a pressure of from about 15-70 psig, or from about 20-65psig, or from about 25-60 psig, or from about 30-55 psig, or from about35-50 psig. In one embodiment, hydrogen is provided at a pressure of40-45 psig. The hydrogenation is carried out at a temperature within therange of from about 25° C. to about 80° C., or from about 30° C. toabout 70° C., or from about 35° C. to about 65° C., or from about 40° C.to about 60° C. In certain embodiments, the hydrogenation is carried outat a temperature within the range of from about 40° C. to about 45° C.The reaction mixture is then cooled to a temperature within the range offrom about 2° C. to about 10° C. and filtered to remove the catalyst.The pH of the filtrate is adjusted and the reaction mixture stirred toallow the resultant crude oxymorphone free base to form a precipitatethat is filtered, washed and dried.

Crude oxymorphone, which contains residual water and, in some instances,can also contain residual ethanol, is dissolved in tert-amyl alcohol andthe solution dried to remove water. This oxymorphone solution is thentreated with excess allyl chloroformate (compound (102)) and sodiumbicarbonate at 70-85° C. (Step 3). Once the reaction is complete (i.e.,conversion of oxymorphone to the 3-allylcarbonate-N-allylcarbamatenoroxymorphone (compound (109)), in which none, some, or all of the14-OH can also be converted to a 14-allylcarbonate group (i.e., compound(110)), water and sodium carbonate are added and, in Step 4A, themixture is heated to 80-85° C. for at least 15 hours to destroy excessallyl chloroformate and to hydrolyze the 3-carbonate moiety as well asany 14-carbonate groups that might be present, providing the17-allylcarbamate derivative of noroxymorphone (compound (105)). Theproduct, noroxymorphone-17-allylcarbamate, can be extracted into asuitable organic solvent which can be filtered, washed, and dried usingnormal work-up procedures. If desired, the product can be recovered byevaporation of that solvent.

In certain embodiments, the reaction of oxymorphone with allylchloroformate can be carried out in the presence of an iodide salt,which can be selected from the group consisting of NaI, KI, LiI, CsI,RuI, MgI₂, CaI₂, NH₄I, tetrabutylammonium iodide, and combinations oftwo or more thereof. In certain embodiments, the iodide salt is NaI. Incertain embodiments, the iodide salt is present in a sub-stoichiometricamount. In certain embodiments, the iodide salt is present in acatalytic amount.

In the decarboxylation reaction, Step 4B, N-allyl carbamatenoroxymorphone (compound (105)) is taken up in an appropriate solvent,e.g., chloroform, and contacted with a transition metal catalyst, e.g.,tetrakis(triphenylphosphine)palladium[0]. The resulting mixture isallowed to stir at a temperature of about 20° C. before being filtered,e.g., through a pad of CELITE. The desired product, naloxone (compound(104)), is then separated from the reaction by normal work-upprocedures.

4.3.4 Further Processes for Conversion of Oxymorphone toNoroxymorphone-17-Allylcarbamate and to Naloxone

In another embodiment, oxymorphone is converted tonoroxymorphone-17-allylcarbamate in two steps, as depicted in Scheme 11.

As provided above, oxymorphone (compound (108)) starting material can beprepared from oripavine (compound (106)) according to the methodsdepicted in Schemes 6 and 10 above, and the productnoroxymorphone-17-allylcarbamate (compound (105)) can be converted tonaloxone (compound (104)) by the transition metal-catalyzeddecarboxylation reactions depicted in Schemes 3, 5, 6, 7, 9, and 10above.

In a further embodiment, oxymorphone can be converted to naloxone asdepicted in Scheme 12.

Although the transition metal catalyst is depicted in Scheme 12 as“Pd[0],” as noted above other transition metal catalysts, including butnot limited to those transition metal catalysts comprising Pd[II],Ni[0], Ni[II], Mo[0], Ru[II], and Rh[I], can be used in those reactions.In another embodiment, the transition metal catalyst comprises 1, 2, 3,or 4 phosphine moieties. In another embodiment, the transition metalcatalyst is tetrakis(triphenylphosphine)palladium[0].

4.4 Preparation of N-Allyl Compounds from Secondary Amines

In certain embodiments, the present disclosure provides transitionmetal-catalyzed reactions for the preparation of N-allyl compounds fromsecondary amines, including, for example, methods for the preparation ofnaloxone from noroxymorphone as depicted in Scheme 13.

In other embodiments, the allylation reaction depicted in Scheme 13 canbe carried out using 1-cyclopropenyl-N,N-dimethylmethanamine orcyclopropenylmethyl acetate to provide the corresponding cyclopropenylderivative of noroxymorphone that can be hydrogenated to providenaltrexone.

In another embodiment, the allylation reaction depicted in Scheme 13 canbe carried out using 1-cyclobutenyl-N,N-dimethylmethanamine orcyclobutenylmethyl acetate to provide the corresponding cyclopropenylderivative of noroxymorphone that again can be hydrogenated to providethe corresponding cyclobutyl derivative of noroxymorphone.

In still other embodiments, the allylation reaction depicted in Scheme13 can be carried out using an allyl haloformate, e.g., allylchloroformate, to provide an allyl carbamate intermediate, or anotherreagent providing a carbamate intermediate that can be converted to anallyl carbamate intermediate, and then converting the allyl carbamate tothe allyl amine in a transition metal-catalyzed reaction.

4.5 Synthesis of Noroxymorphone from Oxymorphone and from Naloxone 4.5.1Synthesis of Noroxymorphone from Naloxone

In another embodiment, the present disclosure provides a method forconversion of oxymorphone and naloxone to noroxymorphone as depicted inScheme 14.

Naloxone (compound (104)) is contacted with an allyl scavenger, e.g.,N,N-dimethyl barbituric acid (compound (146)), and a transition metalcatalyst, e.g., tetrakis(triphenylphosphine)palladium[0], indichloromethane at a temperature of about 20° C. Naloxone as asuspension in dichloromethane is added, and the resulting mixturestirred overnight at a temperature within the range of from about 10° C.to about 70° C., or from about 20° C. to about 60° C., or from about 30°C. to about 60° C. The mixture is cooled and the solids collected byfiltration, washed with dichloromethane, and then washed with water. Thewashed solids are dissolved in aqueous acid (e.g., 10:1water:concentrated sulfuric acid) at a temperature within the range offrom about 10° C. to about 70° C., or from about 20° C. to about 60° C.,or from about 30° C. to about 60° C., and the solution washed withdichloromethane before being basified to a pH within the range of fromabout pH 8 to about pH 10, e.g., using 28% ammonium hydroxide. Thesolids are collected by filtration and dried to provide the desiredproduct, noroxymorphone (see, e.g., Example 7).

In other aspects of this embodiment, for example, oxymorphone is firstconverted to naloxone by the methods depicted in Schemes 10 and 12above, and then to noroxymorphone by the method depicted in Scheme 14,thereby providing an overall process for conversion of oxymorphone tonoroxymorphone.

4.5.2 Synthesis of Noroxymorphone from Oxymorphone

In a further embodiment, naloxone is prepared from oxymorphone in threesteps. In the first step (not depicted in Scheme 15), oxymorphone isdemethylated to provide a first 17-oxycarbonyl derivative (i.e., acompound of formula (71)), e.g., according to the method depicted inScheme 10 above but using a haloformate reagent of the formulaX—C(O)OR⁵⁰, where X is selected from —Cl, —Br, and —I, and in which R⁵⁰is not an allyl moiety. For example, in one embodiment, R⁵⁰ is phenyland, in another embodiment, R⁵⁰ is benzyl. In the second step, the17-oxycarbonyl derivative (compound (71)) is contacted with an alkoxidederivative of an allyl alcohol (i.e., a compound of formula (61)) toprovide a 17-allyloxycarobnyl derivative (e.g., compound (105)) which,in a third step, is decarboxylated in a transition metal-catalyzedreaction, e.g., that of Schemes 3 and 5, to provide naloxone (compound(104)). This embodiment is depicted in Scheme 15.

The methods of the present disclosure are versatile and, as but oneexample, they are readily adapted to provide a process for the synthesisof naltrexone from oripavine, according to the process depicted inScheme 10 above but using, e.g.,

compound (119) as the allyl haloformate reagent for N-demethylation ofoxymorphone, and including a final hydrogenation step to convert thecyclopropene moiety to a cyclopropane group. An illustrative example ofsuch a process is provided in Scheme 16.

In certain embodiments, Step 2 of Scheme 16 can be omitted since the7,8-double bond can be hydrogenated step in Step 5 (see, e.g., Scheme 34below).

4.6 Transition Metal-Catalyzed Reactions for the Synthesis ofCabergoline

In another embodiment, the methods disclosed herein are also useful inprocesses for the synthesis of the potent dopamine receptor agonistcabergoline (compound (125)),

which involve the conversion of the tertiary amine of either lysergol(compound (126)) or elymoclavine (compound (128)) to include the N-allylgroup of cabergoline, using the reagents and methods disclosed herein.

In certain embodiments, therefore, the starting material -eitherlysergol (compound (126)) or elymoclavine (compound (128)) isdemethylated by contact with an allyl haloformate to provide thecorresponding N-allyloxylcarbamate. The N-allyloxylcarbamateintermediates depicted in Schemes 17 and 18 are decarboxylated intransition metal-catalyzed reactions, e.g., those depicted in Schemes 3and 5, to provide the N-allyl product depicted in Schemes 17 and 18. Themethanol group can react with the allyl haloformate reagent, convertingthe hydroxyl group to an allylcarbonate moiety. The allylcarbonate groupcan be converted to the free hydroxyl using methods disclosed herein,e.g., by including a base treatment step (see, e.g., Scheme 10 above) orthrough the transition metal-catalyzed reactions depicted, e.g., inScheme 9 above, to provide the N-allyl products, i.e., compounds (127)and (129), respectively.

In other aspects of this embodiment, lysergol is first hydrogenated toprovide the piperidine derivative depicted below before formation of theN-allyl derivatives thereof, as depicted Scheme 19.

Other synthetic routes useful in a process for production of cybergolinefrom lysergol that employ the transition metal-catalyzed decarboxylationreactions disclosed herein are depicted in Scheme 20.

Elymoclavine could be substituted for lysergol in the methods depictedin Scheme 20 for preparation of cabergoline. In other aspects of thisembodiment, elymoclavine is first hydrogenated to provide the piperidinederivative depicted below before formation of the N-allyl derivativesthereof, as depicted Scheme 21.

Conditions for hydrogenation of lysergol or elymoclavine and theadditional reactions for conversion of the N-allyl derivative disclosedabove to the final product can be found in U.S. Patent ApplicationPublication No. US 2008/0275240 A1 and U.S. Pat. No. 7,217,822 B2, eachof which is hereby incorporated by reference in its entirety.

In certain other, illustrative embodiments, the methods disclosed areused for converting 1-methyl-piperidine and di-iso-propylethylamine tothe corresponding N-allyl derivatives, as depicted in Scheme 22 andScheme 23, respectively.

In certain other, illustrative embodiments, the methods disclosed areused for converting the following tertiary amines to the correspondingsecondary amines or “nor” derivatives: atropine, caffeine, (+)eschscholtzidine, galanthamine, and nicotine, according to Schemes 24through 28.

As depicted, each compound (atropine, caffeine, (+)-eschscholtzidine,galanthamine, and nicotine) can be taken up in an appropriate solvent,e.g., tert-amyl alcohol, and contacted with an allyl haloformate reagent(here allyl chloroformate) to provide the depicted carbamateintermediate. The carbamate intermediates are contacted with atransition metal catalyst in the presence of an allyl scavenger toprovide the demethylated secondary amine or “nor” derivative of eachcompound. In certain embodiments, the tertiary amine is contacted withan allyl haloformate in the presence of an iodide salt. In certainembodiments, the iodide salt is present in a sub-stoichiometric amount.In certain embodiments, the iodide salt is present in a catalyticamount.

In one embodiment, the allyl scavenger can be selected from the groupconsisting of sodium 2-ethylhexonate, morpholine, dimedone,4-methylbenzensulfinic acid, sodium hydroxymethyl sulfinate,benzenesulfinic acid, sodium toluene sulfinate, sodium 2-thiophenesulfinate, tetrabutylammonium toluene sulfinate, N,N-dimethyl barbituricacid, sodium 4-chloro-3-nitrobenzene sulfinate, formic acid, diethylamine, methanol, ethanol, and combinations of two or more thereof. Inanother embodiment, the allyl scavenger is compound (146)

In other embodiments, the allyl haloformate employed in the reactionsdepicted in Schemes 24 through 28 can be prepared from an “allylhaloformate equivalent,” i.e., a compound from which an allylhaloformate can readily be formed, selected from among such compounds asformulae (6), (8), (13), (23), and (46), according to the methodsdisclosed herein, e.g., as depicted in Schemes 11, 12, and 29.

4.7 Method for Making Compounds of Formula (1)

In one embodiment, the present disclosure provides a method for making acompound of formula (1)

in which a tertiary amine of formula (2)

is converted to a carbamate derivative of formula (3)

and the carbamate derivative of formula (3) is contacted with atransition metal catalyst to provide the compound of formula (1). Inspecific aspects of this embodiment, R¹, R², and R³ are eachindependently selected from —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and—(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynyl being unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups,or R¹ and R² are taken together with the nitrogen atom to which they arebound to form a heterocyclic or heteroaryl ring of formula (5)

where n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R⁶ and R⁷ are taken together withthe carbon atoms to which each is bound to form a carbocyclic ring of 3,4, 5, 6, 7, 8, or 9 carbon atoms, the carbocyclic ring beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I, phenyl,or —(C₁-C₆) alkyl; and R⁵¹ is —(C₁-C₆) alkyl or an oxygen protectinggroup. In certain embodiments, R⁶ and R⁷ are taken together with thecarbon atoms to which each is bound to form a carbocyclic ring of 3, 4,5, or 6 carbon atoms, the carbocyclic ring being unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups; R⁸is —OR⁵¹, —F, —Cl, —Br, —I, phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is—(C₁-C₆) alkyl or an oxygen protecting group. For example, R⁶ and R⁷taken together can form a methylene (i.e., —CH₂—) which, combined withthe carbon atom to which R⁶ and R⁷ are attached, provides athree-membered cyclopropenyl ring, e.g., as contained in the compound offormula (18) when p is 1.

In certain other embodiments, n is an integer selected from 0, 1, 2, 3,4, 5, 6, and 7. In further embodiments, n is an integer selected from 0,1, 2, 3, 4, and 5. In a particular embodiment, n is an integer selectedfrom 0, 1, 2, and 3. In another particular embodiment, n is 3.

The heterocyclic or heteroaryl ring of formula (5) is a monocyclic ringthat is saturated, unsaturated non-heteroaryl, or heteroaryl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁵² groups, or is a subunit of a polycyclic ringsystem comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic,heterocyclic, aryl, or heteroaryl rings, each of which is unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups.R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, —C(═O)(C₁-C₆)alkyl, and —(C₁-C₆) alkyl, each alkyl being either unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³ groups;and R⁵³ is —H or an oxygen protecting group. Accordingly, compounds offormula (2) include, e.g., opioid compounds. In certain embodiments, R⁵²is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, and —(C₁-C₆) alkyl,where each alkyl group is either unsubstituted or substituted with 1, 2,3, 4, or 5 independently-selected —OR⁵³ groups; and R⁵³ is —H or anoxygen protecting group.

Among the three R groups (R′, R², and R³) attached to the nitrogen atomof the tertiary amine of formula (1), the group removed in thedealkylation reaction can be predicted according to the followinghierarchy: benzyl>allyl>cycloxhexyl>methyl (see, e.g., Cooley et al.,“Amine Dealkylations with Acyl Chlorides” (1989) Synthesis 1-7). Incertain embodiment, e.g., those in which each of R′, R², and R³ is analkyl group, it may be predicted that the least sterically hinderedmoiety will be the group displaced in the dealkylation reaction. Inaddition, where R′ and R² are taken together with the nitrogen atom towhich they are bound to form a heterocyclic or heteroaryl ring offormula (5)

where n is as defined above, then it can be predicted that R³ would bethe chemical group removed in the dealkylation reaction. Moreover, theheterocyclic or heteroaryl ring of formula (5) is a monocyclic ring thatis saturated, unsaturated non-heteroaryl, or heteroaryl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁵² groups, or is a subunit of a polycyclic ringsystem comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic,heterocyclic, aryl, or heteroaryl rings, each of which is unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups.R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, —C(═O)(C₁-C₆)alkyl, and —(C₁-C₆) alkyl, each alkyl group being either unsubstitutedor substituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³groups; and R⁵³ is —H or an oxygen protecting group. In certainembodiments, R⁵² is selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, and—(C₁-C₆) alkyl, where each alkyl group is either unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³ groups;and R⁵³ is —H or an oxygen protecting group.

Compounds disclosed herein can contain one or more asymmetric centersand can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. In reference to compounds of formula (1) forexample, as well as all other compounds described herein that containone or more olefinic double bonds or other centers of geometricasymmetry, unless specified otherwise, it is intended to include both Eand Z geometric isomers. The method disclosed herein can be used witheach of the enantiomers, diastereomers, and other stereoisomeric formsof the reagents disclosed herein to provide each of the enantiomers,diastereomers, and other stereoisomeric forms of the products disclosedherein.

The transition metal catalyst mediating the decarboxylation of thecompound of formula (3) to provide the compound of formula (1) can beselected from the group consisting of Pd(PPh₃)₄, Pd(Ph₂P(CH₂)₄PPh₂)₂,Ni(PPh₃)₄, Ni(Ph₂P(CH₂)₄PPh₂)₂, ((pentamethylcyclopentadienyl)RuCl)₄,[Pd(DBA)₂]/PPh₃, [Pd(OAc)₂]/PPh₃, [Ni(COD)₂]/PPh₃, NiCl₂/PPh₃,Ni[P(OEt)₃]₄, [Mo(CO)₆-DPPE], RhH(PPh₃)₄—P(n-Bu)₃, and combinations oftwo or more thereof. In another embodiment, the transition metalcatalyst comprises 1, 2, 3, or 4 phosphine moieties. In anotherembodiment, the transition metal catalyst istetrakis(triphenylphosphine)palladium[0].

The transition metal catalyst is present in an amount which enables thereaction to proceed. In certain embodiments, the transition metalcatalyst is present in a sub-stoichiometric amount. In certainembodiments, the transition metal catalyst is present in a catalyticamount. In certain embodiments, the transition metal catalyst is presentin an amount of from 0.001 to 30 mol % or of any numerical value withinthis range. In certain embodiments, the transition metal catalyst ispresent in an amount of from 0.1 to 10 mol % or of any numerical valuewithin this range (like about 5 mol %).

4.7.1 Method for Making Compound of Formula (3): Reaction With AllylHaloformates

In one embodiment, the compound of formula (3) is prepared by contactingthe compound of formula (2) with a compound of formula (93)

where X can be selected from —Cl, —Br, and —I, in a solvent. In certainembodiments, the contacting the compound of formula (2) with a compoundof formula (93) is carried out in the presence of a base. In certainembodiments, the reaction between the compound of formula (2) and thecompound of formula (93) is carried out in solvent that can be selectedfrom the group consisting of CHCl₃, CH₂Cl₂, 1,2-dichloroethane, toluene,THF, ethyl acetate, acetone, tert-amyl alcohol, tert-butyl alcohol,3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol,2-methyl-2-hexanol, acetonitrile, benzene, carbon tetrachloride,chlorobenzene, 1,2-dichlorobenzene, DMF, trifluorotoluene, 1,4-dioxane,1,2-dimethoyxethane, xylene, and combinations of two or more thereof.

In particular embodiments, the solvent comprises, consists essentially,or is (i.e., consists of) a tertiary alcohol selected from the groupconsisting of tert-amyl alcohol, tert-butyl alcohol,3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol,2-methyl-2-hexanol, and combinations of two or more thereof. In aspecific embodiment, the solvent comprises tert-amyl alcohol. In anotherspecific embodiment, the solvent consists essentially of tert-amylalcohol. In another specific embodiment, the solvent is tert-amylalcohol.

In certain embodiments, the reaction between the compound of formula (2)and the compound of formula (93) is carried out in the presence of abase selected from the group consisting of Na₂CO₃, NaHCO₃, KHCO₃, K₂CO₃,Cs₂CO₃, and combinations of two or more thereof.

In certain embodiments, the compound of formula (93) or its equivalent,e.g., an “allyl haloformate equivalent,” is added to the reactionmixture containing the compound of formula (2) in a single portion. Inother embodiments, the compound of formula (93) is added in a pluralityof portions or portion-wise to the reaction mixture containing thecompound of formula (2) throughout the course of the reaction (e.g., seeExamples 3 and 18 below). For example, the compound of formula (93) canbe added in 2, 3, 4, 5, 6, 7, 8, 9, 10, or more distinct portionsthroughout the course of the reaction. The individual quantities of thecompound of formula (93) in each portion can be the same or different.Portions of the compound of formula (93) can be added at well-definedintervals during the reaction. For example, individual portions of thecompound of formula (93) can be added about every 1 to 26 hours, aboutevery 20 hours, or about every 16 hours as the reaction progresses.Alternatively, individual portions of the compound of formula (93) canbe added at times during the reaction when the rate of formation of thedesired product(s) diminishes.

In another embodiment, the compound of formula (93) or its equivalent,e.g., an “allyl haloformate equivalent,” is added continuously to thereaction mixture containing the compound of formula (2) throughout thecourse of the reaction. In another embodiment, continuous addition isachieved by preparing a solution of the compound of formula (93) in thereaction solvent, e.g., a dilute solution in one embodiment, adding thedilute solution to an addition funnel, and slowly dropping the dilutesolution into the reaction mixture containing the compound of formula(2). In another embodiment, continuous addition is achieved by filling ahypodermic syringe equipped with a mechanically-driven plunger with thedilute solution of the compound of formula (93) and adding the dilutesolution through a hypodermic needle into the reaction mixturecontaining the compound of formula (2). In another embodiment,continuous addition is achieved by using a continuous or semi-continuousreactor in which the compound of formula (93) is added to a streamcontaining the compound of formula (2). The volume of the dilutesolution, the concentration of the dilute solution, and/or the rate atwhich the dilute solution is added to the reaction mixture can be varieddepending on the time needed for the reaction to achieve substantialcompletion.

Methods of carrying out portion-wise and continuous addition of a liquidreagent to a reaction mixture are known in the art. For example, U.S.Pat. Nos. 2,191,786, 2,583,420, 3,355,486, 3,749,646, 4,217,787,6,486,692, and 6,994,827, each of which is hereby incorporated byreference in its entirety, disclose chemical reactors in which onereagent is added incrementally to a solution containing additionalreagents. Incremental addition is known in the art as the metering-in ofa reagent over a finite period of time in contrast with the dumping ofthe total reagent into the reactor at once. The term incrementaladdition includes addition using a continuous stream, addition using avariable stream, addition intermittently using separate portions, andother related methods. See U.S. Pat. No. 4,217,287 (col. 2, lines56-62).

In certain embodiments, a stoichiometric excess of the compound offormula (93) or its equivalent, e.g., an “allyl haloformate equivalent,”is added relative to the compound of formula (2). The stoichiometric(molar) ratio, i.e., the total amount of the compound of formula (93) tothe total amount of the compound of formula (2), can vary from about1.2:1 to about 20:1 in one embodiment, from about 1.8:1 to about 9:1 inanother embodiment, from about 1.9:1 to about 7:1 in another embodiment,and from about 1.9:1 to about 4.5:1 in another embodiment. It has beendiscovered that for embodiments in which the compound of formula (93) isadded portion-wise or continuously throughout the course of thereaction, the quantity of the compound of formula (93) required to reacha desired level of conversion to the compound of formula (3) is reducedrelative to embodiments where the full amount of the compound of formula(93) is added only in the beginning of the reaction. In theseportion-wise or continuous embodiments, the stoichiometric (molar) ratioof the compound of formula (93) to the compound of formula (2) rangesfrom about 1.9:1 to about 7:1 in one embodiment, from about 1.9:1 toabout 4.5:1 in another embodiment, from about 1.5:1 to about 3:1 inanother embodiment, and from about 1.5:1 to about 2.2:1 in anotherembodiment. Thus, the overall molar ratio of the compound of formula(93) to the compound of formula (2) needed to produce the desired yieldof the compound of formula (3) can be reduced. Minimizing the quantityof the compound of formula (93) employed can be advantageous when thatcompound possesses undesirable properties, e.g., allyl chloroformate(compound (102)), which is flammable, toxic, and not easily handledand/or disposed of.

4.7.2 Method for Making Compounds of Formula (3): β-Carbon Eliminationof a Single Leaving Group

In another embodiment, the compound of formula (3) is prepared bycontacting the compound of formula (2) with a compound of formula (6)

in which one of Y and Y′ is a leaving group and the other is —H, in asolvent to provide a compound of formula (7)

The compound of formula (7) can be converted to the compound of formula(3) as disclosed herein.

In particular aspects of this embodiment, the leaving group is selectedfrom —Cl, —Br, —I, —OS(O)₂C₄F₉, —OS(O)₂CF₃, —OS(O)₂F, -para-toluenesulfonate, and —OS(O)₂CH₃. In certain embodiments, the leaving group isa halogen selected from —Cl, —Br, and —I. In other embodiments, theleaving group is —Br.

In certain embodiments, the contacting of a compound of formula (2) witha compound of formula (6) is carried out in the presence of a base,which can, e.g., be selected from the group consisting of Na₂CO₃,NaHCO₃, KHCO₃, K₂CO₃, Cs₂CO₃, and combinations of two or more thereof.

In certain embodiments, conversion of the compound of formula (7) to thecompound of formula (3) is carried out under conditions and/or in thepresence of a reagent that promotes elimination of the leaving group, Yor Y′. In one aspect of this embodiment, elimination of the leavinggroup Y is promoted by heat. In another aspect, elimination of theleaving group Y is promoted by exposure to light of an appropriatewavelength. In a further aspect, elimination of the leaving group Y ispromoted by including a reagent that is a base. Where the reagent is abase, it can, for example, be selected from the group consisting ofNaOH, KOH, sodium tert-butoxide (tert-BuONa), potassium tert-butoxide(tert-BuOK), lithium di-iso-propylamide, sodium hydride, tert-butyllithium, LiAlH₄, AlCl₃, triethylamine, sodium ethoxide, lithium diethylamide (LiN(Et)₂), potassium acetate (KOAc), and combinations of two ormore thereof.

The reaction is carried out in a suitable solvent that, e.g., can beselected from the group consisting of DMSO, 2-methyl-propan-2-ol,benzene, hexane, THF, 1,4-dioxane, DMF, diethylether, acetone, methanol,ethanol, toluene, and combinations of two or more thereof.

4.7.3 Method for Making Compounds of Formula (3): α,β-Carbon Eliminationof Two Leaving Groups

In one aspect of this embodiment, the compound of formula (3) isprepared by elimination of two leaving groups (Z and Z′) from a compoundof formula (9)

to provide the compound of formula (3), where Z and Z′ are each leavinggroups independently selected from —Cl, —Br, and —I. In certainembodiments, Z and Z′ are each —Br while, in other embodiments, Z and Z′are each —Cl. Elimination of leaving groups Z and Z′ is carried out inthe presence of a transition metal catalyst by contacting the compoundof formula (9) under conditions and/or in the presence of a reagent thatpromotes elimination of the leaving groups to provide the compound offormula (3). In one illustrative embodiment, Z and Z′ are each —Br andelimination of both Br atoms is carried out in the presence of apromoting reagent, e.g., ethylmagnesium bromide and tributyltin hydride.In certain embodiments, the catalyst is, for example, nickeldiphenylphosphinoethane dichloride [Ni(DPPE)Cl₂]. This reaction can becarried out in a solvent selected, e.g., from among THF andacetonitrile, at temperature within the range of from about −20° C. toabout 40° C.

In one embodiment, the compound of formula (9) can be formed bycontacting a compound of formula (2) with a compound of formula (8)

where X is selected from —Cl, —Br, and —I, in a solvent in the presenceof base to provide the compound of formula (9).

This reaction can be carried out in a solvent selected from the groupconsisting of CHCl₃, CH₂Cl₂, 1,2-dichloroethane, toluene, THF, ethylacetate, acetone, tert-amyl alcohol, tert-butyl alcohol,3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol,2-methyl-2-hexanol, acetonitrile, benzene, carbon tetrachloride,chlorobenzene, 1,2-dichlorobenzene, DMF, trifluorotoluene, 1,4-dioxane,1,2-dimethoyxethane, xylene, and combinations of two or more thereof.

In particular embodiments, the solvent comprises, consists essentially,or is (i.e., consists of) a tertiary alcohol selected from the groupconsisting of tert-amyl alcohol, tert-butyl alcohol,3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol,2-methyl-2-hexanol, and combinations of two or more thereof.

In a specific embodiment, the solvent comprises tert-amyl alcohol. Inanother specific embodiment, the solvent consists essentially oftert-amyl alcohol. In another specific embodiment, the solvent istert-amyl alcohol.

This reaction can be carried out in the presence of a base, which can,e.g., be selected from the group consisting of Na₂CO₃, NaHCO₃, KHCO₃,K₂CO₃, Cs₂CO₃, and combinations of two or more thereof. In certainembodiments, the base is selected from the group consisting of NaHCO₃,KHCO₃, and combinations thereof.

4.7.4 Method for Making Compounds of Formula (3): Carbamate/AllylAlcohol Exchange

In another embodiment, compounds of formula (3) are prepared in twosteps. In the first, a compound of formula (2) is contacted with ahaloformate compound of formula (10)

to provide a carbamate of formula (11)

The compound of formula (11) is then contacted with an alkoxidederivative of an allyl alcohol of formula (12)

to provide the compound of formula (3). In one aspect of thisembodiment, the alkoxide derivative is a compound of formulaNaO—CH₂CH═CH₂ (i.e., a compound of formula (61) in which M is Na).

In one embodiment, the alkoxide derivative is NaO—CH₂CH═CH₂ which isprepared by reacting sodium with a 15-30 fold molar excess ofHO—CH₂CH═CH₂ to provide an alkoxide solution which is contacted with asolution of a compound of formula (11), and the mixture is heated at100° C. for four hours and then allowed to stand at a temperature ofabout 20° C. for about 16 hours.

4.7.5 Method for Making Compounds of Formula (3): Alkyne Hydrogenation

In another embodiment, the compound of formula (3) is prepared bycontacting the compound of formula (2) with a haloformate of formula(13)

to provide a compound of formula (14)

and then selectively hydrogenating the compound of formula (14) toprovide an allyl carbamate derivative of formula (16)

which is a compound of formula (3) in which R⁶ and R⁷ are each hydrogen.The compound of formula (16) can be converted to a compound of formula(15)

using the transition metal-catalyzed, decarboxylation reactionsdisclosed herein.

In one embodiment, reduction (hydrogenation) of the alkyne to the alkeneis carried out in methanol with hydrogen and quinoline in the presenceof 5% Lindlar catalyst. In another embodiment, the reduction is carriedout in the presence of 1.0 M NaBH₄, hydrogen, diethyl amine andNi[II]acetate in aqueous methanol (see also U.S. Pat. No. 6,335,459,which is hereby incorporated by reference in its entirety.).

4.8 Method for Making Compounds of Formula (17)

In a further embodiment, the compound of formula (1) is a compound offormula (17)

which can be prepared by contacting a compound of formula (2) with acompound of formula (19)

to provide a compound of formula (18)

which is a compound of formula (3).

In certain embodiments, the compound of formula (19) is prepared in twosteps which will be described using cyclopropene-1-methanol as exemplarycompound in the following. In the first step, cyclopropene-1-methanol

(compound (141)) is synthesized from1,1,2-tribromocyclopropane-2-methanol as described by Dulayymi et al.(1996) Tetrahedron 52(10):3409-3424, which is hereby incorporated byreference in its entirety. The cyclopropene-1-methanol is then reactedwith phosgene to provide the following chloroformate reagent

(compound (119)), which is a compound of formula (19) in which X is Cl,p is 1, and R⁴ and R⁵ are each H. Condensation of an allyl alcohol withphosgene is a typical method that can be used to provide thecorresponding allyl chloroformate reagents that can be used todealkylate tertiary amines. However, other methods and reagents can beutilized for the conversion of an allyl alcohol to the correspondinghaloformate reagent. The resulting allyl carbamate derivatives can bedecarboxylated using the transition metal-catalyzed reactions disclosedherein to provide N-allyl derivatives in which in allyl moiety of theallyl alcohol has been substituted for an alkyl group of the tertiaryamine.

The compound of formula (18) can be contacted with a transition metalcatalyst to provide the compound of formula (17). In certainembodiments, p is 1 and the compound of formula (17) has the followingstructure:

while, in other embodiments, p is 2 and the compound of formula (17) hasthe following structure:

4.9 Method for Making Compounds of Formula (20)

In a further embodiment, the present disclosure provides a method formaking a compound of formula (20)

in which a compound of formula (2) is contacted with a compound offormula (21)

in a solvent to provide a compound of formula (22)

In certain embodiments, the contacting of the compound of formula (2)with the compound of formula (21) is carried out in the presence of abase. X can be selected from —Cl, —Br, and —I. In a particularembodiment, X is —I. In that particular embodiment, the compound offormula (21) is compound of formula (21′), i.e.,

and the compound of formula (22) is compound of formula (22′), i.e.,

The compound of formula (22) can then be decarboxylated in a transitionmetal-catalyzed reaction to provide the compound of formula (20).

In certain embodiments, the compound of formula (21) has the followingchemical structure:

(where X is —I, the previous molecule is compound (142)), that isprepared by reacting an alcohol of the following formula

(where X is —I, the previous molecule is compound (143)) with phosgeneto provide the depicted chloroformate ((Z)-4-iodobut-2-enylcarbonochloridate). For example, the alcohol ((Z)-4-iodobut-2-en-1-ol),can be prepared as described by Balas et al. (2009) J. Med. Chem.52:1005-1017, which is hereby incorporated by reference in its entirety.Again, condensation of an allyl alcohol with phosgene is a typicalmethod that can be used to provide the corresponding allyl chloroformatereagents that can be used to dealkylate tertiary amines. However, othermethods and reagents for conversion of an allyl alcohol to thecorresponding haloformate reagent can also be used. The resulting allylcarbamate derivatives can be decarboxylated using the transitionmetal-catalyzed reactions disclosed herein to provide N-allylderivatives in which in allyl moiety of the allyl alcohol has beensubstituted for an alkyl group of the tertiary amine.

4.10 Method for Making Compounds of Formula (1): β-Carbon Elimination

The present disclosure also provides a method for making compounds offormula (1) that includes transition metal-catalyzed reaction in which acompound of formula (24)

is converted to a compound of formula (1). In one illustrativeembodiment, a compound of formula (2) is contacted with a compound offormula (23)

in a solvent to provide the compound of formula (24), where V is aleaving group. In certain embodiments, the contacting of the compound offormula (2) and the compound of formula (23) is carried out in thepresence of a base.

The compound of formula (24) is contacted with a transition metalcatalyst to provide an allyl carbamate intermediate of formula (3)

which is then decarboxylated to the corresponding N-allyl derivative

a compound of formula (1), in a second transition metal-catalyzedreaction.

Applicants believe, without wishing to be held to that belief, that thereactions of this embodiment involve the intermediates depicted belowand proceed with both a metal insertion reaction and a β-hydrideelimination, as depicted in the following Scheme 29, illustrated with anexemplary palladium-containing transition metal catalyst.

As indicated in Scheme 29, a compound of formula (24)

is contacted with a transition metal catalyst, which can insert into theindicated bond to provide an intermediate of formula (72)

that undergoes β-hydride elimination to provide an intermediate offormula (3)

which in turn, reacts with the transition metal catalyst present in thereaction mixture to provide the decarboxylated N-allyl compound offormula (1)

The reactions of Scheme 29 therefore provide a “single step” transitionmetal-catalyzed process for the preparation of compounds of formula (1)from compounds of formula (24) (e.g., see Scheme 12 which illustratesthe use of the reactions of Scheme 29 for the preparation of, e.g.,compound (104), naloxone).

The leaving group V, can be selected, for example, from among —Cl, —Br,—I, —OS(O)₂C₄F₉, —OS(O)₂CF₃, —OS(O)₂F, -para-toluene sulfonate,—OS(O)₂CH₃, and —B(O(C₁-C₄) alkyl)₂.

4.11 Method for Making Compounds of Formula (1): Allylation of SecondaryAmines

In a further embodiment, compounds of formula (1) are prepared bycontacting a compound of formula (25)

with a compound of formula (26)

where R⁴⁰ is —OC(O)CH₃ or —N(CH₃)₂, in a solvent in the presence of atransition metal catalyst.

In certain embodiments, R⁴⁰ is —O(C)OX where X is selected from —Cl,—Br, and —I.

In one embodiment, allylation of noroxymorphone with allyl acetate isaccomplished by combining noroxymorphone with triethylamine (3equivalents), toluene (50 mL) andtetrakis(triphenylphosphine)palladium[0] (0.1 equivalent), and heatingthe mixture at 80° C. for 64 hours. The mixture is cooled to atemperature of about 20° C. and filtered through a plug of CELITE andthe filtrate was concentrated under reduced pressure. Naloxone isisolated from the concentrated filtrate using normal extractiveprocedures.

In certain embodiments, allylation of noroxymorphone withdimethylallylamine is accomplished by combining noroxymorphone,1,4-bis(diphenylphosphino)-butane (0.1 equivalent), palladium[II]acetate (0.05 equivalent), acetic acid (2 equivalents), and DMF (40 mL)and stirring the mixture at 50° C. for 16 hours.

4.12 Method for Making Compounds of Formula (27)

The present disclosure also provides a method for making compounds offormula (27)

in which a compound of formula (2) is contacted with a compound offormula (19)

to provide a compound of formula (18)

The compound of formula (18) is then decarboxylated in the presence of atransition metal catalyst to provide a compound of formula (17)

which is then hydrogenated to provide the compound of formula (27).Variable p is an integer selected from 1, 2, 3, 4, 5, 6, and 7. Where pis 1, the compound of formula (27) is a compound of the followingformula

(formula (28)), and where p is 2, the compound of formula (27) is acompound of the following formula

As noted above, compounds of formula (19) can be prepared in two steps.The unsaturated alcohols, e.g.,

(compound (141)), can be prepared as described by Dulayymi et al. (1996)Tetrahedron 52(10):3409-3424, which is hereby incorporated by referencein its entirety. Those alcohols can then reacted with phosgene toprovide the haloformate reagents of formula (19). Other methods andreagents can also be used for conversion of an allyl alcohol to thecorresponding haloformate reagent of formula (19).

Haloformate reagents of formula (19) are condensed with a tertiary amineof formula (2) as described in Examples 1 and 2, below, to provide thecarbamate intermediates of formula (18) that are decarboxylated intransition metal-catalyzed reactions, as described in Examples 4, 5 and6, to provide compounds of formula (17). Hydrogenation of the compoundsof formula (17) is carried out, in one embodiment, in the presence ofprecious metal catalyst, which can be dispersed on a solid support,e.g., Pd/C or Pt/C, under a hydrogen atmosphere. Hydrogenation can alsobe accomplished using additional methods disclosed herein including,without limitation, transfer hydrogenation.

4.13 Method for Making Compounds of Formula (28)

The present disclosure also provides a method for making a compound offormula (28)

in which a compound of formula (2) is contacted with a compound offormula (29)

to provide a carbamate derivative of formula (30)

which is decarboxylated in a transition metal-catalyzed reaction toprovide a compound of formula (31)

The compound of formula (31) is then contacted with a zinc-containingreagent, e.g., zinc[0], in the presence of an iodide salt to provide thecompound of formula (28). X is a halogen selected from —Cl, —Br, and —I.In specific embodiments, X is —I.

In certain embodiments, the iodide salt is present in asub-stoichiometric amount. In certain embodiments, the iodide salt ispresent in a catalytic amount.

Compounds of formula (29) are prepared by condensation of thecorresponding alcohol with phosgene as noted above, where the alcohol isprepared according to the methods disclosed by Balas et al. (2009) J.Med. Chem. 52:1005-1017. The zinc-promoted allyl iodide cyclizationwhereby compounds of formula (31) are converted to compounds of formula(28) are carried out according to the method disclosed by Sakuma et al.(2005) Tetrahedron 61:10138-10145, which is hereby incorporated byreference in its entirety. In certain embodiments, compounds of formula(31) are contacted with zinc powder (3 equivalents) in 2:1tert-butanol/H₂O at reflux temperature under an argon atmosphere for 0.5hours to about 24 hours. Once the reaction is deemed to be complete, themixture can be filtered and the solvent removed by evaporation. Thedesired compounds of formula (28) are then isolated using standardchromatographic methods and equipment.

4.14 Method for Making Compounds of Formula (32)

Processes for the preparation of compound of formula (32)

are also provided. These processes include contacting a compound offormula (2) with a haloformate reagent of formula (93) to provide acompound of formula (3) as described, e.g., in Section 4.7 above, andthe compound of formula (3), in turn is converted to a compound offormula (1), using the methods disclosed herein. The compound of formula(1) can then be converted to a compound of formula (32) as depicted inScheme 30 and as described below.

In one embodiment, the compound of formula (1) is contacted withmeta-chloroperbenzoic acid or ortho-chloroperbenzoic acid to provide acompound of formula (33)

a compound of formula (32) in which W is 0.

In one embodiment, compounds of formula (1) are taken up in a solventand contacted with from about 1 equivalent to about 6 equivalents ofm-chloro peroxybenzoic acid at a temperature within the range of fromabout 0° C. to about 40° C. for a period of time within the range offrom about 0.5 hours to about 24 hours. In certain embodiments, thesolvent is methylene chloride while, in other embodiments, the solventis benzene or a mixture of benzene and methylene chloride. In certainembodiments, the reaction is carried out at about 20° C.

In another embodiment, the compound of formula (33) is contacted withNaN₃ and NH₄Cl to provide a compound of formula (34)

which is

contacted with, e.g., PPh₃, to provide a compound of formula (35)according to the methods disclosed by Chiappe et al. (1998) Asymmetry9:4079-4088, which is hereby incorporated by reference in its entirety.

In certain embodiments, the compound of formula (33) is taken up inmethanol:water (4:1) and NaN₃ (4.5 equivalents) and NH₄Cl (2.5equivalents) added. The mixture is stirred at 80° C. and the reactionmonitored until deemed complete, e.g., 18-20 hours. The intermediateazido alcohols of formula (34) can be recovered using normal work-upprocedures. The recovered material can then be taken up in a suitablesolvent, e.g., acetonitrile, and PPh₃ added (1 equivalent). The mixtureis stirred at about 20° C. until the evolution of gas (N₂) is observedand then at reflux temperature overnight (about 16 hours). The desiredproduct of formula (35) is isolated and characterized using normalwork-up procedures and analytical methodology.

In a still further embodiment, the compound of formula (1) is contactedwith compound (144)

in the presence of iso-propylCu(dibenzoylmethane) and iodosylbenzene toprovide a compound of formula (36)

according to the methods disclosed by Xu et al. (2008) Org. Lett.10(7):1497-1500 and Guthikonda et al. (2002) J. Am. Chem. Soc.124:13672-13673, which are hereby incorporated by reference in theirentireties.

In one embodiment, the compound of formula (1) is taken up inchlorobenzene and reacted with 10% IPrCu(dibenzoylmethane),iodosobenzene (PhIO) (1.5 equivalents), and trichloroethylsulfamateester at about 25° C. for about 12 to about 30 hours, or until such timeas the reaction is deemed complete, under an inert atmosphere, e.g., anitrogen atmosphere. Once the reaction is deemed complete, the desiredproduct of formula (36) is isolated and characterized using normalwork-up procedures and analytical methodology.

In another embodiment, the compound of formula (1) is contacted withCHI₃ and CrCl₂ to provide a compound of formula (37)

and the compound of formula (37) is contacted with a zinc-containingreagent, e.g., zinc[0], in the presence of acetic acid to provide acompound of formula (38)

according to the methods disclosed in Takai et al. (2003) J. Am. Chem.Soc. 125:12990-12991, which is hereby incorporated by reference in itsentirety.

In another embodiment, the compound of formula (1) is taken up in THF,and CHI₃ (1.5 equivalents), CrCl₂ (4 equivalents), andN,N,N′,N′-tetraethylethylenediamine (TEEDA) are added. The reaction iscarried out at about 25° C. until deemed complete. The product, acompound of formula (37), is isolated and characterized using normalwork-up procedures and analytical methodology. Removal of the iodidegroup, converting the compound of formula (37) to a compound of formula(38), is accomplished by contacting the former compound with zinc inacetic acid, according to methods disclosed in Martin et al. (1994) J.Am. Chem. Soc. 116:4493-4494, which is hereby incorporated by referencein its entirety.

In another embodiment, the compound of formula (1) is contacted withCH₂I₂ to provide the compound of formula (38) directly, according tomethods disclosed in U.S. Patent Application Publication No. US2007/0142634 A1, and Aggarwal et al. (2003) Org. Lett. 5(23):4417-4420,each of which is hereby incorporated by reference in its entirety. Inone embodiment, the compound of formula (1) is taken up in methylenechloride at 0° C. and contacted with the zinc-containing reagent diethylzinc (5 equivalents) followed by diiodomethane (10 equivalents). Thereaction is warmed to a temperature of about 20° C. and stirred forabout 16 hours. The reaction is quenched and the desired product offormula (38) is isolated and characterized using normal work-upprocedures and analytical methodology. In other embodiments, thezinc-containing reagent can be selected from the group consisting ofdiethyl zinc, zinc dust, zinc-copper couple, and combinations thereof.

4.15 Method for Making Compounds of Formula (39)

The present disclosure also provides a method for making a compound offormula (39), in which a compound of formula (1), prepared by theprocesses disclosed in section 4.7 above, is hydrogenated to provide thecompound of formula (39)

In certain embodiments, the compound of formula (1) is taken up in asuitable solvent, a catalyst added, and the mixture contacted with ahydrogen atmosphere at a temperature and for a time sufficient toconvert the compound of formula (1) to a compound of formula (39). Inrepresentative embodiments, the solvent is selected from the groupconsisting of ethanol, methanol, dichloromethane, 1:1ethylacetate:methanol, THF, and combinations of two or more thereof. Thecatalyst, for example, can be selected from the group consisting ofpalladium on carbon (Pd/C), platinum on carbon (Pt/C), and combinationsthereof. The hydrogen pressure is typically between 15 psi and 60 psi.The hydrogenation is typically carried out at a temperature betweenabout 15° C. and 30° C. for a period of time of from about 1 hour toabout 24 hours.

4.16 Method for Making Compounds of Formula (40)

In another embodiment, the present disclosure provides a process formaking compounds of formula (40)

in which compounds of formula (1), prepared by the processes disclosedin section 4.7 above, are oxidized to provide the compound of formula(40). In certain embodiments, the oxidation is carried out in thepresence of osmium tetroxide and N-methyl morpholine N-oxide. In oneembodiment, the compound of formula (1) is taken up 1:1 water:THF andcontacted with 0.025 equivalents of osmium tetroxide and 15 equivalentsof N-methyl morpholine N-oxide for a time within the range of from about6 hours to about 30 hours, or within the range of from about 12 to about24 hours, and at a temperature within the range of from about 10° C. toabout 30° C., or a temperature within the range of from about 15° C. toabout 25° C. In certain embodiments, the reaction is carried out for 18hours at a temperature of 20° C.

4.17 Method for Making Compounds of Formula (41)

As noted above, the present disclosure provides processes for preparingN-allyl amines from tertiary N-alkyl amines involving, inter alia,haloformate-promoted N-dealkylation of a tertiary amine (e.g., acompound of formula (2)) and a subsequent transition metal-catalyzedallylic decarboxylation (e.g., of a compound of formula (3)) to providethe N-allyl amine (e.g., a compound of formula (1)). The processesdisclosed herein are also useful for preparing N-allyl amines fromcompounds (tertiary amines) comprising the structural elements ofcompounds of formula (2), e.g., from alkaloids, and more particularly,from opioids.

Accordingly, in a particular embodiment, the present disclosure providesa method for making compound of formula (41)

in which a compound of formula (95)

is contacted with a transition metal catalyst in a solvent to providethe compound of formula (41), where R¹⁴ and R¹⁶ are each independentlyselected from —OH, —H, and —OR¹⁷; R¹⁵ is selected from —OH, —H, —OR¹⁷,═O, and ═CH₂; and R¹⁷ is an oxygen protecting group. As discussed above,e.g., in connection with the compound of formula (95), R^(14′), R^(15′),and R^(16′) are as defined previously.

In a particular embodiment, R¹⁴ and R¹⁶ are each —OH, and R¹⁵ is ═O, andtherefore the compound of formula (41) is naloxone.

In one embodiment of this method, R^(14′) is selected from—OC(O)OCH₂CH═CH₂, and —OH and R¹⁶ is —OH. In another embodiment, R¹⁴,R^(14′), R¹⁶, and R^(16′) are each —OH and R¹⁵ and R^(15′) are each ═O.

In a further embodiment, the transition metal catalyst is selected fromthe group consisting of Pd(PPh₃)₄, Pd(Ph₂P(CH₂)₄PPh₂)₂, Ni(PPh₃)₄,Ni(Ph₂P(CH₂)₄PPh₂)₂, ((pentamethylcyclopentadienyl)RuCl)₄,[Pd(DBA)₂]/PPh₃, [Pd(OAc)₂]/PPh₃, [Ni(COD)₂]/PPh₃, NiCl₂/PPh₃,Ni[P(OEt)₃]₄, [Mo(CO)₆-DPPE], RhH(PPh₃)₄—P(n-Bu)₃, and combinations oftwo or more thereof. In another embodiment, the transition metalcatalyst comprises 1, 2, 3, or 4 phosphine moieties. In anotherembodiment, the transition metal catalyst istetrakis(triphenylphosphine)palladium[0].

In certain embodiments, the transition metal catalyst is present in asub-stoichiometric amount. In certain embodiments, the transition metalcatalyst is present in a catalytic amount. In certain embodiments, thetransition metal catalyst is present in an amount of from 0.001 to 30mol % or of any numerical value within this range. In certainembodiments, the transition metal catalyst is present in an amount offrom 0.1 to 10 mol % or of any numerical value within this range (likeabout 5 mol %).

In another embodiment, the decarboxylation reaction is carried out in asolvent selected from the group consisting of CHCl₃, CH₂Cl₂,1,2-dichloroethane, toluene, THF, ethyl acetate, acetone, tert-amylalcohol, tert-butyl alcohol, 3-methyl-3-pentanol,2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol,acetonitrile, benzene, carbon tetrachloride, chlorobenzene,1,2-dichlorobenzene, DMF, trifluorotoluene, 1,4-dioxane,1,2-dimethoyxethane, xylene, and combinations of two or more thereof.

In certain embodiments, the oxygen protecting group, R¹⁷, is selectedfrom the group consisting of tert-butyl-diphenylsilyl,tert-butyl-dimethylsilyl, trimethylsilyl, tri-iso-propylsilyl,tert-butyldimethylsilyloxymethyl, β-methoxyethoxymethyl,[bis-(4-methoxyphenyl)phenylmethyl)], methoxymethyl, para-methoxybenzyl,methylthiomethyl, pivaloyl, methyl, ethoxyethyl, triphenylmethyl,—C(O)(C₁-C₄) alkyl, —C(O)OR¹⁸, and —(C₁-C₆) alkyl, each alkyl beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R²¹ groups; R¹⁸ is —(C₁-C₆) alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynyl beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R²¹ groups; and each R²¹ is independentlyselected from —OH, —Cl, —Br, —I, —NH₂, —CN, and phenyl.

4.17.1 Method for Making Compounds of Formula (41): 3-Ether Hydrolysis

In another embodiment, the present disclosure provides a method formaking a compound of formula (41), in which moiety R¹⁴ is —OH, therebyproviding a compound of formula (44)

In this embodiment, the compound of formula (44) can be prepared bycontacting a compound of formula (43)

with base to provide the compound of formula (44), where R¹⁶ is selectedfrom —OH, —H, and —OR¹⁷; R¹⁵ is selected from —OH, —H, —OR¹⁷, ═O, and═CH₂; and R¹⁷ is an oxygen protecting group. In certain embodiments, R¹⁵is ═O and R¹⁶ is —OH and, therefore, the compound of formula (44) isnaloxone.

In particular embodiments, the base is selected from the groupconsisting of Na₂CO₃, NaHCO₃, KHCO₃, K₂CO₃, Cs₂CO₃, NaOH, KOH, LiOH, andcombinations of two or more thereof.

In other embodiments, the allyl ether, e.g., of compound (143), can becleaved (1) in the presence of Pd/C, para-toluene sulfonic acid in wateror methanol at a temperature within the range of from about 60° C. toabout 80° C. for about 6 hours (see, e.g., Boss et al. (1976) Angw.24Chem., Int. Ed., Engl. 15:558); (2) in the presence of seleniumdioxide/acetic acid in dioxane at reflux temperature for about one hour(see, e.g., Kariyone et al. (1970) Tetrahedron Lett. 11(33):2885-2888);(3) in the presence of NaAlH₂(OCH₂CH₂OCH₃), in toluene at refluxtemperature for about ten hours (see, e.g., Kametani et al. (1976) J.Org. Chem. 41:2545); (4) in the presence of Ph₃P/Pd(OAc)₂ in formic acidat about 90° C. for one hour (see, e.g., Hey et al. (1973) Angew. Chem.,Int. Ed., Engl. 12:928); (5) in the presence of a Pd[0] catalyst,Bu₃SnH, in acetic acid and para-nitrophenol (see, e.g., Four et al.(1982) Tetrahedron Lett. 23:1825); (6) in the presence of Pd(Ph₃P)₄ andLiBH₄ in THF (see, e.g., Bois-Choussey et al. (1996) J. Org. Chem.61:9309); in this embodiment, NaBH₄ can also be used as an allylscavenging agent (see, e.g., Beugelmans et al. (1994) Tetrahedron Lett.35:4349); (7) in the presence of Pd(Ph₃P)₄ and PhSiH₃ for about 0.5hours (see, e.g., Dessolin et al. (1995) Tetrahedron Lett. 36:5741); (8)in the presence of bis(benzonitrile)palladium (II) chloride, in benzeneat reflux temperature for from about 16 hours to about 20 hours (see,e.g., Bruce et al., “Cleavage of Allyl Phenyl Ethers byBis(benzonitrile)palladium (II) Chloride” (July 1981) J. Chem. Res.Synop. No. 7, p. 193); (9) in the presence of RhCl₃ in ethanol at refluxtemperature (see, e.g., Martin et al. (1982) J. Org. Chem. 47:1513);(10) in the presence of LiPPh₂ in THF at reflux temperature for aboutfour hours (see, e.g., Mann et al., “761. The Dealkylation of Alkyl ArylEthers and Sulphides by Diaryl-phosphide and -arsenide Ions” (1965) J.Chem. Soc. pp. 4120-4127); (11) in the presence of SiCl₄ and NaI, inCH₂Cl₂ and acetonitrile for about eight hours (see, e.g., Bhatt et al.(December 1982) Synthesis 12:1048-1050); and (12) in the presence ofNaBH₄ and I₂ in THF at 0° C. (see, e.g., Thomas et al. (1997)Tetrahedron Lett. 38:4721). Each of the references cited is herebyincorporated by reference in its entirety.

4.17.2 Method for Making Compounds of Formula (41): Allyl Haloformate

In another embodiment, the present disclosure provides a method formaking a compound of formula (41)

in which a compound of formula (45)

is contacted with a compound of formula (48)

in a solvent comprising a base to provide a compound of formula (95)

which can be decarboxylated in the transition metal-catalyzed reactiondescribed in Section 4.3.1 to provide a compound of formula (41), whereR¹⁴, R^(14′), R¹⁵, R^(15′), R¹⁶, R^(16′), and X are defined as above. Asdiscussed above, for a carbonate-containing group present at R^(14′),R^(15′), and/or R^(16′), formed from an R¹⁴, R¹⁵, and/or R¹⁶ —OH group,respectively, that carbonate-containing group can be converted back tothe —OH group.

In certain embodiments, the base is selected from the group consistingof Na₂CO₃, NaHCO₃, KHCO₃, K₂CO₃, Cs₂CO₃, NaOH, KOH, LiOH, andcombinations of two or more thereof.

In certain embodiments, solvent is selected from the group consisting ofCHCl₃, CH₂Cl₂, 1,2-dichloroethane, toluene, THF, ethyl acetate, acetone,tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol,2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol,acetonitrile, benzene, carbon tetrachloride, chlorobenzene,1,2-dichlorobenzene, DMF, trifluorotoluene, 1,4-dioxane,1,2-dimethoyxethane, xylene, and combinations of two or more thereof.

In particular embodiments, the solvent is selected from the groupconsisting of tert-amyl alcohol, tert-butyl alcohol,3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol,2-methyl-2-hexanol, and combinations of two or more thereof. In aspecific embodiment the solvent is tert-amyl alcohol.

In certain embodiments, the iodide salt is present in asub-stoichiometric amount. In certain embodiments, the iodide salt ispresent in a catalytic amount. In another embodiment, the reaction iscarried out in the presence of a catalytic amount of an iodide saltwhich can be selected from, e.g., NaI, KI, LH, CsI, RuI, MgI₂, CaI₂,NH₄I, tetrabutylammonium iodide, and combinations of two or morethereof. In certain embodiments, the iodide salt is NaI.

4.17.3 Method for Making Compounds of Formula (41): 13-CarbonElimination of a Leaving Group

In another embodiment, the present disclosure provides a method formaking a compound of formula (41), in which a compound of formula (45)

is contacted with a compound of formula (46)

to provide a compound of formula (47)

where R¹⁴, R^(14′), R¹⁵, R^(15′), R¹⁶, R^(16′), X, and Y are defined asabove. In certain embodiments, the leaving group Y is selected from —Cl,—Br, —I, —OS(O)₂C₄F₉, —OS(O)₂CF₃, —OS(O)₂F, -para-toluene sulfonate, and—OS(O)₂CH₃. In a specific embodiment, Y is —Cl.

In certain embodiments, the compound of formula (47) is converted to acompound of formula (42) under conditions and/or in the presence of areagent that promotes elimination of the leaving group, Y. In one aspectof this embodiment, elimination of the leaving group Y is promoted byheat. In another aspect, elimination of the leaving group Y is promotedby exposure to light of an appropriate wavelength. In a further aspect,elimination of the leaving group Y is promoted by including a reagentthat is a base. Where the reagent is a base, it can, for example, beselected from the group consisting of NaOH, KOH, tert-BuONa, tert-BuOK,lithium di-iso-propylamide, sodium hydride, tert-butyl lithium, LiAlH₄,AlCl₃, triethylamine, sodium ethoxide, LiN(Et)₂, KOAc, and combinationsof two or more thereof.

The compound of formula (42) can be decarboxylated in the transitionmetal-catalyzed reaction described in Section 4.3.1 to provide acompound of formula (41). In certain embodiments, the base is selectedfrom the group consisting of NaOH, KOH, tert-BuONa, tert-BuOK, lithiumdi-iso-propylamide, sodium hydride, tert-butyl lithium, LiAlH₄, AlCl₃,triethylamine, sodium ethoxide, LiN(Et)₂, KOAc, and combinations of twoor more thereof.

4.17.4 Method for Making Compounds of Formula (41): 3-CarbamateHydrolysis

In another embodiment, the present disclosure provides a method formaking a compound of formula (41) comprising the step of contacting acompound of formula (49)

with base to provide a compound of formula (50)

which is a compound of formula (42) in which R¹⁴ is —OH. In a particularembodiment, R¹⁵ is ═O and R¹⁶ is —OH.

4.17.5 Method for Making Compounds of Formula (41): Carbamate Exchange

In a further embodiment, the present disclosure also provides a methodfor making compounds of formula (41), which comprises contacting acompound of formula (45)

with a compound of formula (10)

to provide a compound of formula (60)

wherein R¹⁴, R^(14′), R¹⁵, R^(15′), R¹⁶, R^(16′), and X are defined asabove.

The compound of formula (60) is contacted with an alkoxide derivativecompound of formula (61)

to provide the compound of formula (95)

In this embodiment, R⁹ is selected from phenyl and 4-nitro-phenyl;R^(14′), R^(15′), and R^(16′) are defined as above and M is selectedfrom the group consisting of Na, K, and Li. The compound of formula (95)can be converted to the compound of formula (42)

by basic hydrolysis. The compound of formula (42) can be decarboxylatedin a transition metal-catalyzed reaction as described in Section 4.3.1above, to provide a compound of formula (41).

Formation of the alkoxide derivative compound of formula (61) andconditions for the reaction of the alkoxide derivative compound offormula (61) with the compound of formula (60) to provide the compoundof formula (42) can be carried out according to the methods disclosed byVillani et al. (1986) Arzneim-Forsch./Drug Res. 36(11), No. 9:1311-1314,which is hereby incorporated by reference in its entirety. Accordingly,in one embodiment, the alkoxide derivative is NaO—CH₂CH═CH₂ and it isprepared by reacting sodium with a 15-30 fold molar excess ofHO—CH₂CH═CH₂to provide an alkoxide solution which is contacted with asolution of a compound of formula (60), and the mixture is heated at100° C. for four hours and then allowed to stand at a temperature ofabout 20° C. for about 16 hours, to provide as the desired product acompound of formula (42).

4.18 Method for Making Compounds of Formula (41): β-Carbon Eliminationof a Leaving Group

In another embodiment, the present disclosure provides a method formaking compounds of formula (41), in which a compound of formula (47)

is contacted with a transition metal catalyst in a solvent to providethe compound of formula (41), where R¹⁴, R^(14′), R¹⁵, R^(15′), R¹⁶,R^(16′), and Y are defined as above. The leaving group Y can be selectedfrom —Cl, —Br, —I, —OS(O)₂C₄F₉, —OS(O)₂CF₃, —OS(O)₂F, -para-toluenesulfonate, and —OS(O)₂CH₃. In a specific embodiment, Y is —Cl. Asdiscussed above, for a carbonate-containing group present at R^(14′),R^(15′), and/or R^(16′), formed from an R¹⁴, R¹⁵, and/or R¹⁶ —OH group,respectively, that carbonate-containing group can be converted back tothe —OH group before the addition of the transition metal catalyst.

The oxygen protecting group, R¹⁷, can be selected from the groupconsisting of consisting tert-butyl-diphenylsilyl,tert-butyl-dimethylsilyl, trimethylsilyl, tri-iso-propylsilyl,tert-butyldimethylsilyloxymethyl, β-methoxyethoxymethyl,[bis-(4-methoxyphenyl)phenylmethyl)], methoxymethyl, para-methoxybenzyl,methylthiomethyl, pivaloyl, methyl, ethoxyethyl, triphenylmethyl,—C(O)(C₁-C₄) alkyl, —C(O)OR²⁴, and —(C₁-C₆) alkyl, each alkyl beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R²⁵ groups; R²⁴ is —(C₁-C₆) alkyl, —(C₂-C₆)alkenyl, or —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynyl beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R²⁵ groups; and each R²⁵ is independentlyselected from —OH, —Cl, —Br, —I, —NH₂, —CN, and phenyl.

In certain embodiments of this method, the transition metal catalyst isselected from the group consisting of Pd(PPh₃)₄, Pd(Ph₂P(CH₂)₄PPh₂)₂,Ni(PPh₃)₄, Ni(Ph₂P(CH₂)₄PPh₂)₂, ((pentamethylcyclopentadienyl)RuCl)₄,[Pd(DBA)₂]/PPh₃, [Pd(OAc)₂]/PPh₃, [Ni(COD)₂]/PPh₃, NiCl₂/PPh₃,Ni[P(OEt)₃]₄, [Mo(CO)₆-DPPE], RhH(PPh₃)₄—P(n-Bu)₃, and combinations oftwo or more thereof. In another embodiment, the transition metalcatalyst comprises 1, 2, 3, or 4 phosphine moieties. In anotherembodiment, the transition metal catalyst istetrakis(triphenylphosphine)palladium[0].

In particular embodiments of this method, R^(14′) and R^(16′) are eachindependently selected from —OH and —OC(O)O(CH₂)₃Y, and R¹⁵ is ═O.

Further embodiments of this method comprise

(a) reacting a compound of formula (45)

with a compound of formula (46)

to provide a compound of formula (47)

(b) optionally, converting the compound of formula (47) to the compoundof formula (94)

(c) converting the compound of formula (47) or the compound of formula(94) to a compound of formula (42)

and

(d) converting the compound of formula (42) to the compound of formula(41), where R¹⁴, R^(14′), R¹⁵, R^(15′), R¹⁶, R^(16′), X, and Y aredefined as above.

In alternative embodiments and as discussed above, for acarbonate-containing group present at R^(14′), R^(15′), and/or R^(16′),formed from an R¹⁴, R¹⁵, and/or R¹⁶ —OH group, respectively, thatcarbonate-containing group can be converted back to the —OH group afterthe decarboxylation step.

4.18.1 Method for Making Compounds of Formula (47)

In certain embodiments of this method, the compound of formula (47) isprepared by contacting a compound of formula (45)

with a compound of formula (46)

to provide the compound of formula (47)

in which R¹⁴, R^(14′), R¹⁵, R^(15′), R¹⁶, R^(16′), X, and Y are definedas above.

In particular embodiments, the leaving group Y is selected from —Cl,—Br, —I, —OS(O)₂C₄F₉, —OS(O)₂CF₃, —OS(O)₂F, -para-toluene sulfonate, and—OS(O)₂CH₃. In a specific embodiment, Y is —Cl.

In other embodiments, R¹⁷ is an oxygen protecting group selected fromthe group consisting of tert-butyl diphenylsilyl, tert-butyldimethylsilyl, trimethylsilyl, tri-iso-propylsilyl,tert-butyldimethylsilyloxymethyl, β-methoxyethoxymethyl,[bis-(4-methoxyphenyl)phenylmethyl)], methoxymethyl, para-methoxybenzyl,methylthiomethyl, pivaloyl, methyl, ethoxyethyl, triphenylmethyl,—C(O)(C₁-C₄) alkyl, —C(O)OR²⁴, and —(C₂-C₆) alkyl, each alkyl beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R²⁵ groups; R²⁴ is —(C₁-C₆) alkyl, —(C₂-C₆)alkenyl, or —C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynyl beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R²⁵ groups; and each R²⁵ is independentlyselected from —OH, —Cl, —Br, —I, —NH₂, —CN, and phenyl.

4.19 Method for Making Compounds of Formula (45)

In certain embodiments of the methods disclosed above, the compound offormula (45)

is a compound of formula (51)

i.e., a compound of formula (45) in which R¹⁵ is ═O and R²⁶ is —OH.

In a further embodiment, the compound of formula (51), is prepared byoxidizing a compound of formula (52)

to provide a compound of formula (53)

and hydrogenating the compound of formula (53) to provide the compoundof formula. (51).

In one aspect of this embodiment, R¹⁴ is —OH. In another aspect of thisembodiment, R¹⁴ is —OCH₃.

In one embodiment, the compound of formula (52) is oxidized to theproduct of formula (53) with performic acid, which can be prepared insitu by mixing hydrogen peroxide and excess formic acid. The reaction iswarmed to a temperature within the range of from about 20° C. to about80° C., or within the range of from about 30° C. to about 70° C., orwithin the range of from about 40° C. to about 60° C., and maintained atthat temperature for a time sufficient to allow the starting material tobe consumed. In certain embodiments, the reaction is carried out at atemperature of about 50° C. for about two hours.

The oxidized product, a compound of formula (53), can be taken as thecrude product of the oxidation reaction directly on to the next step(hydrogenation of the 7,8-double bond) without purification. In thisembodiment, the crude compound of formula (53) is hydrogenated in thepresence of a catalyst under a hydrogen atmosphere at a temperaturewithin the range of from about 10° C. to about 75° C., or within therange of from about 25° C. to about 65° C., or within the range of fromabout 30° C. to about 55° C. In certain embodiments, the hydrogenationis carried out at a temperature within the range of from about 40° C. toabout 45° C. The catalyst can be, e.g., a palladium or a platinumcatalyst and can be dispersed on a solid support as, e.g., Pd/C or Pt/C.Once the reaction is deemed complete, the mixture is then cooled to atemperature within the range of from about 2° C. to about 10° C. andfiltered to remove the catalyst. The pH of the filtrate is adjusted andthe reaction mixture stirred to allow the resultant crude compound offormula (51) as the free base to form a precipitate that is filtered,washed, and dried.

4.20 Method for Making Compounds of Formula (54)

The present disclosure also provides methods for making compounds offormula (54)

which comprise contacting a compound of formula (55)

with a compound of formula (56)

in a solvent comprising a base and a transition metal catalyst toprovide the compound of formula (54).

In this embodiment, R¹⁴ and R¹⁶ are each independently selected from—OH, —H, and —OR¹⁷; and the 6,7

bond, the 7,8

bond, and the 8,14

bond are each independently a single bond or a double bond, with theprovisos that (1) if the 6,7

bond is a double bond, then the 7,8

bond is a single bond, (2) if the 7,8

bond is a double bond, then the 6,7

and 8,14

bonds are each a single bond, and (3) if the 8,14

bond is a double bond, then the 7,8

bond is a single bond and R¹⁶ is not present.

In this embodiment, R¹⁵ is selected from —OH, —H, —OR¹⁷, ═O, and ═CH₂with the proviso that if the 6,7

bond is a double bond, then R¹⁵ is selected from —OH, —H, and —OR¹⁷; andR¹⁷ is an oxygen protecting group. In this embodiment, R²² is selectedfrom —N(CH₃)₂, —OC(O)CH₃, and —OC(O)X; and X is selected from —Cl, —Br,and —I. In another embodiment, R²² is selected from —N(CH₃)₂ and—OC(O)CH₃. In another embodiment, R²² is —OC(O)X.

In this embodiment, the transition metal catalyst is selected from thegroup consisting of Pd(PPh₃)₄, Pd(Ph₂P(CH₂)₄PPh₂)₂, Ni(PPh₃)₄,Ni(Ph₂P(CH₂)₄PPh₂)₂, ((pentamethylcyclopentadienyl)RuCl)₄,[Pd(DBA)₂]/PPh₃, [Pd(OAc)₂]/PPh₃, [Ni(COD)₂]/PPh₃, NiCl₂/PPh₃,Ni[P(OEt)₃]₄, [Mo(CO)₆-DPPE], RhH(PPh₃)₄—P(n-Bu)₃, and combinations oftwo or more thereof. In another embodiment, the transition metalcatalyst comprises 1, 2, 3, or 4 phosphine moieties. In anotherembodiment, the transition metal catalyst istetrakis(triphenylphosphine)palladium[0].

In this embodiment, the base is selected from the group consisting ofNa₂CO₃, NaHCO₃, KHCO₃, K₂CO₃, Cs₂CO₃, and combinations of two or morethereof.

In this embodiment, R¹⁷ is an oxygen protecting group selected from thegroup consisting of tert-butyl-diphenylsilyl, tert-butyl-dimethylsilyl,trimethylsilyl, tri-iso-propylsilyl, tert-butyldimethylsilyloxymethyl,β-methoxyethoxymethyl, [bis-(4-methoxyphenyl)phenylmethyl)],methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, methyl,ethoxyethyl, triphenylmethyl, —C(O)(C₁-C₄) alkyl, —C(O)OR²⁴, and—(C₂-C₆) alkyl, each alkyl being unsubstituted or substituted with 1, 2,3, 4, or 5 independently-selected R²⁵ groups; R²⁴ is —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, or —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R²⁵ groups; and each R²⁵ is independentlyselected from —OH, —Cl, —Br, —I, —NH₂, —CN, and phenyl.

In one embodiment, the 6,7

bond, the 7,8

bond, and the 8,14

bond is each a single bond. In another embodiment, the 7,8

bond is a double bond; and the 6,7

and 8,14

bonds are each a single bond. In another embodiment, the 6,7

and 8,14

bonds are each a double bond; the 7,8

bond is a single bond; R¹⁶ is not present; and R¹⁵ is selected from —OH,—H, and —OR¹⁷.

In another embodiment, the 6,7

bond, the 7,8

bond, and the 8,14

bond is each a single bond; and R¹⁵ is selected from —OH, —OR¹⁷, and ═O.In another embodiment, the 7,8

bond is a double bond; and the 6,7

and 8,14

bonds are each a single bond; R¹⁵ is selected from —OH, —OR¹⁷, and ═O;and R¹⁴ and R¹⁶ are each independently selected from —OH and —H. Inanother embodiment, the 6,7

and 8,14

bonds are each a double bond, the 7,8

bond is a single bond, R¹⁶ is not present, and R¹⁵ is —OR¹⁷.

In one embodiment of this method, the 6,7

and 8,14

bonds are each a double bond and R¹⁵ is —OCH₃.

In one embodiment, R²² is selected from —N(CH₃)₂, and —OC(O)CH₃. Inanother embodiment R²² is —OC(O)X; and X is —Br, —Cl, or —I.

In one aspect of this embodiment, R¹⁴ is —OH. In another aspect of thisembodiment, R¹⁴ is —OCH₃.

4.21 Method for Making Compounds of Formula (57)

The present disclosure also provides a method for making compounds offormula (57)

which comprises contacting a compound of formula (42)

with a transition metal catalyst in the presence of an allyl scavengerto provide the compound of formula (57). In this embodiment, R¹⁴ and R¹⁶are each independently selected from —OH, —H, and —OR¹⁷; R′⁵ is selectedfrom —OH, —H, —OR¹⁷, ═O, and ═CH₂; and R¹⁷ is an oxygen protectinggroup. The allyl scavenger is selected from the group consisting ofsodium 2-ethylhexonate, morpholine, dimedone, 4-methylbenzensulfinicacid, sodium hydroxymethyl sulfinate, benzenesulfinic acid, sodiumtoluene sulfinate, sodium 2-thiophene sulfinate, tetrabutylammoniumtoluene sulfinate, N,N-dimethyl barbituric acid, sodium4-chloro-3-nitrobenzene sulfinate, formic acid, diethyl amine, methanol,ethanol, and combinations of two or more thereof.

In another embodiment, the compound of formula (57) is prepared bycontacting a compound of formula (41)

with a transition metal catalyst in the presence of an allyl scavengerto provide the compound of formula (57), where R¹⁴ and R¹⁶ are eachindependently selected from —OH and —H; R¹⁵ is selected from —OH, —H,—OR¹⁷, ═O, and ═CH₂; and R¹⁷ is an oxygen protecting group. The allylscavenger can be selected from the group consisting of sodium2-ethylhexonate, morpholine, dimedone, 4-methylbenzensulfinic acid,sodium hydroxymethyl sulfinate, benzenesulfinic acid, sodium toluenesulfinate, sodium 2-thiophene sulfinate, tetrabutylammonium toluenesulfinate, N,N-dimethyl barbituric acid, sodium 4-chloro-3-nitrobenzenesulfinate, formic acid, diethyl amine, methanol, ethanol, andcombinations of two or more thereof.

In one embodiment, the compound of formula (41) is taken up indichloromethane and N,N-dimethyl barbituric acid (0.5 to 1.0equivalents) and tetrakis(triphenylphosphine)palladium[0] (0.05equivalents), and the reaction mixture is stirred at about 20° C. andthen at about 40° C. for 16 hours. Once the reaction is deemed complete,the mixture is cooled to a temperature of about 20° C. and the solidsfiltered under reduced pressure. The solids can be washed withdichloromethane and then with water before being taken up in a 10:1mixture of water:concentrated sulfuric acid at 40° C. The warmed aqueoussolution is washed with dichloromethane and then basified to a pH of9.05 with 28% ammonium hydroxide. The resulting solids are filtered anddried under reduced pressure at 100° C. for 20 hours to yield theproduct, a compound of formula (57).

4.22 Method for Making Compounds of Formula (58)

The present disclosure also provides a method for making compounds offormula (58)

in which a compound of formula (59)

is contacted with a transition metal catalyst in a solvent in thepresence of an allyl scavenging reagent (“allyl scavenger”) to providethe compound of formula (58), where R¹⁶ is selected from —OH, —H, and—OC(O)CH₂CH═CH₂; R¹⁵ is selected from —OH, —H, —OR¹⁷, ═O, and ═CH₂; andR¹⁷ is an oxygen protecting group.

In one embodiment, the allyl scavenger can be selected from the groupconsisting of sodium 2-ethylhexonate, morpholine, dimedone,4-methylbenzensulfinic acid, sodium hydroxymethyl sulfinate,benzenesulfinic acid, sodium toluene sulfinate, sodium 2-thiophenesulfinate, tetrabutylammonium toluene sulfinate, N,N-dimethyl barbituricacid, sodium 4-chloro-3-nitrobenzene sulfinate, formic acid, diethylamine, methanol, ethanol, and combinations of two or more thereof. Inanother embodiment, the allyl scavenger is compound (146)

4.23 Method for Making Compounds of Formula (42)

In a further embodiment, the present disclosure also provides a methodfor making compounds of formula (42), which comprises contacting acompound of formula (45)

with a compound of formula (10)

to provide a compound of formula (60)

The compound of formula (60) is contacted with an alkoxide derivativecompound of formula (61)

to provide a compound of formula (95). In this embodiment, R⁹ isselected from phenyl and 4-nitro-phenyl; R¹⁴, R^(14′), R¹⁵, R^(15′),R¹⁶, R^(16′), X, and M are defined as above. The compound o formula (60)can then be converted to the compound of formula (42) by converting anycarbonate groups present to —OH groups.

In one embodiment, the alkoxide derivative is NaO—CH₂CH═CH₂ which isprepared by reacting sodium with a 15-30 fold molar excess ofHO—CH₂CH═CH₂ to provide an alkoxide solution which is contacted with asolution of a compound of formula (60), and the mixture is heated at100° C. for four hours and then allowed to stand at a temperature ofabout 20° C. for about 16 hours to provide the compound of formula (42).The compound of formula (42) can be then be decarboxylated in atransition metal-catalyzed reaction as described in Section 4.3.1 aboveto provide a compound of formula (41).

4.24 Method for Making Compounds of Formula (62)

The present disclosure further provides a method for making compounds offormula (62)

comprising

(a) contacting a compound of formula (45)

with a compound of formula (63)

in a solvent comprising a base to provide a compound of formula (64)

(b) optionally, converting any carbonate group at R^(14′), R^(15′), orR^(16′) to an —OH group to provide a compound of formula (96)

(c) contacting the compound of formula (64) or the compound of formula(96) with a transition metal catalyst to provide a compound of formula(65)

and

(d) hydrogenating the compound of formula (65) to provide a compound offormula (62). In this embodiment, R¹⁴, R^(14′), R¹⁵, R^(15′), R¹⁶,R^(16′), and X are defined as above. The compound of formula (65) can behydrogenated, e.g., by contact with a hydrogen atmosphere in thepresence of an appropriate catalyst, e.g., Pd/C or Pt/C.

In one aspect of this embodiment, p is 1. In another aspect of thisembodiment, p is 2.

In certain embodiments, the compound of formula (63) is prepared in twosteps. In the first, an alkene containing-1-methanol derivative of thefollowing formula

is synthesized from a tribromocyclic-2-methanl compound in a manneranalogous that described for use of the corresponding1,1,2-tribromocyclopropane-2-methanol of Dulayymi et al. (1996)Tetrahedron 52(10):3409-3424, which is hereby incorporated by referencein its entirety. The alcohol is then reacted with phosgene to providethe corresponding chloroformate reagent compound of formula (73)

i.e., the compound of formula (63) where X is Cl.

4.25 Method for Making Compounds of Formula (66)

The present disclosure also provides a method for making a compound offormula (66)

which comprises

(a) contacting a compound of formula (45)

with a compound of formula (67)

to provide a compound of formula (68)

(b) optionally, converting the carbonate groups present at R^(14′),R^(15′), and R^(16′) to —OH groups to provide the compound of formula(97)

(c) contacting the compound of formula (68) or the compound of formula(97) with a transition metal catalyst to provide a compound of formula(69)

and

(d) contacting the compound of formula (69) with a zinc-containingreagent, e.g., zinc[0], to provide the compound of formula (66). Inthese embodiments, R¹⁴, R^(14′), R¹⁵, R^(15′), R¹⁶, R^(16′), and X, aredefined as above. In certain embodiments, the compound of formula (68)is one in which X is —I.

In alternative embodiments, any carbonate groups present at R^(14′),R^(15′), and/or R^(16′) can be converted to —OH groups after thedecarboxylation step.

In certain embodiments, the contacting is carried out in the presence ofan iodide salt. The iodide salt can be selected from, e.g., NaI, KI,LiI, CsI, RuI, MgI₂, CaI₂, NH₄I, tetrabutylammonium iodide, andcombinations of two or more thereof. In certain embodiments, the iodidesalt is NaI. In certain embodiments, the iodide salt is present in asub-stoichiometric amount. In certain embodiments, the iodide salt ispresent in a catalytic amount.

In certain embodiments, the compound of formula (67) has the followingchemical structure

(compound (142)) and is prepared by reacting an alcohol of the followingformula

(compound (143)) with phosgene to provide the depicted chloroformate:(Z)-4-iodobut-2-enyl carbonochloridate. The alcohol(Z)-4-iodobut-2-en-1-ol can be prepared as described by Balas et al.(2009) J. Med. Chem. 52:1005-1017, which is hereby incorporated byreference in its entirety.

4.26 Processes for the Preparation of Compounds of Formulae (74), (75),(88), and (89)

In other illustrative embodiments, the present disclosure providesmethods for the synthesis of compounds of formula (74) and formula (75).More specifically, the present disclosure provides a method for making acompound of formula (74)

comprising

(a) contacting a compound of formula (76)

with a compound of formula (93)

in a solvent to provide a compound of formula (77)

(b) optionally, converting a carbonate group at R^(59′) to an —OH groupto provide a compound of formula (99)

(c) converting the compound of formula (77) or the compound of formula(99) to a compound of formula (78)

and

(d) contacting the compound of formula (78) with a compound of formula(79) X—R⁵⁸ to provide the compound of formula (74), where the

bond is a single bond or a double bond. In certain embodiments, thesolvent comprises a tertiary alcohol while, in other embodiments, thesolvent consists essentially of a tertiary alcohol.

In this embodiment, R⁵⁹ is selected from —OH, —H, and —OR¹⁷; R⁵⁴ isselected from —H, —CH₃, —OH, and —OR¹⁷; R′⁷ is an oxygen protectinggroup; and R⁵⁸ is selected from allyl, methyl cyclopropyl, methylcyclobutyl, and propargyl.

As used throughout herein, it is to be understood that R^(59′) includesnot only R⁵⁹ but also, when an R⁵⁹ group is present as an —OH group, thereaction product of a compound of formula (48) or its equivalent, e.g.,an “allyl haloformate equivalent,” with that —OH group to form a groupcomprising a carbonate. Thus, R^(59′) groups include, in addition to therespective R⁵⁹ groups, such carbonate-containing reaction products. Evenfurther, certain reaction pathways described herein convert thecarbonate portion of the carbonate-containing reaction product into anether group. Thus, R^(59′) further includes such ether-containingreaction products.

It is also to be understood that when R⁵⁹ is selected to be a particularmoiety that is not an —OH group, then R^(59′) is also that particularR⁵⁹ moiety.

In embodiments where an R^(59′) group is a carbonate-containing groupformed from an —OH group, that carbonate-containing group can beconverted back to the —OH group. Conversion of the carbonate-containinggroup to the —OH group can be carried out in the presence of a suitablebase. Alternatively, when an R^(59′) group is an allyl carbonate, thatallyl carbonate can first be converted into an —O-allyl group through atransition metal catalyzed decarboxylation reaction, in accordance withthe present disclosure. Thereafter, the —O-allyl group can be convertedinto an —OH group in the presence of a suitable allyl scavenger, asdescribed herein.

R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl, phenyl,allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl, -2-butynyl,-3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R⁶ and R⁷ are taken together withthe carbon atoms to which each is bound to form a carbocyclic ring of 3,4, 5, 6, 7, 8, or 9 carbon atoms, the carbocyclic ring beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I, phenyl,or —(C₁-C₆) alkyl; and R⁵¹ is —(C₁-C₆) alkyl or an oxygen protectinggroup. Each X is independently selected from —Cl, —Br, and —I. Incertain embodiments, R⁶ and R⁷ are taken together with the carbon atomsto which each is bound to form a carbocyclic ring of 3, 4, 5, or 6carbon atoms, the carbocyclic ring being unsubstituted or substitutedwith 1, 2, 3, 4, or 5 independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F,—Cl, —Br, —I, phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is —(C₁-C₆) alkyl or anoxygen protecting group.

In certain embodiments, the tertiary alcohol is selected from the groupconsisting of tert-amyl alcohol, tert-butyl alcohol,3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol,2-methyl-2-hexanol, and combinations of two or more thereof. In aparticular embodiment, the tertiary alcohol is tert-amyl alcohol.

In certain embodiments, conversion of the compound of formula (77) tothe compound of formula (78) comprises contacting the compound offormula (77) with a transition metal catalyst in the presence of anallyl scavenger to provide the compound of formula (78). Suitablereaction conditions for this conversion are analogous to or readilyadapted from those of Example 7 and correspond to the reactions depictedin Schemes 24 through 28.

In certain embodiments, the allyl scavenger is selected from the groupconsisting of sodium 2-ethylhexonate, morpholine, dimedone,4-methylbenzensulfinic acid, sodium hydroxymethyl sulfinate,benzenesulfinic acid, sodium toluene sulfinate, sodium 2-thiophenesulfinate, tetrabutylammonium toluene sulfinate, N,N-dimethyl barbituricacid, sodium 4-chloro-3-nitrobenzene sulfinate, formic acid, diethylamine, methanol, ethanol, and combinations of two or more thereof.

The present disclosure also provides a method for making a compound offormula (75)

comprising

(a) contacting a compound of formula (80)

with a compound of formula (93)

in a solvent to provide a compound of formula (81)

(b) optionally, converting a carbonate group at R^(59′) to an —OH groupto provide a compound of formula (100)

(c) converting the compound of formula (81) or the compound of formula(100) to a compound of formula (82)

and

(d) contacting the compound of formula (82) with a compound of formula(79) X—R⁵⁸ to provide the compound of formula (75), where the

bond is a single bond or a double bond. In certain embodiments, thesolvent comprises a tertiary alcohol while, in other embodiments, thesolvent consists essentially of a tertiary alcohol. R⁵⁹, R^(59′), R⁴,R⁵, R⁶, R⁷, and X are defined as above.

In certain embodiments, conversion of the compound of formula (81) orthe compound of formula (100) to the compound of formula (82) comprisescontacting the compound of formula (81) or the compound of formula (100)with a transition metal catalyst in the presence of an allyl scavengerto provide the compound of formula (82). Suitable reaction conditionsfor this conversion are analogous to or readily adapted from those ofExample 7 and correspond to the reactions depicted in Schemes 24 through28.

In certain embodiments, the allyl scavenger is selected from the groupconsisting of sodium 2-ethylhexonate, morpholine, dimedone,4-methylbenzensulfinic acid, sodium hydroxymethyl sulfinate,benzenesulfinic acid, sodium toluene sulfinate, sodium 2-thiophenesulfinate, tetrabutylammonium toluene sulfinate, N,N-dimethyl barbituricacid, sodium 4-chloro-3-nitrobenzene sulfinate, formic acid, diethylamine, methanol, ethanol, and combinations of two or more thereof.

The tertiary alcohol can be selected from the group consisting oftert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol,2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol, andcombinations of two or more thereof. In certain embodiments, thetertiary alcohol is tert-amyl alcohol.

In certain embodiments of these methods for making compounds of formula(74) and formula (75), R⁵⁸ is methyl cyclopropyl, the

bond is a single bond, R⁵⁹ is —OH, and R⁵⁴ is —OCH₃.

In certain embodiments of these methods for making compounds of formula(74) and formula (75), each oxygen protecting group, R¹⁷, can beindependently selected from the group consisting oftert-butyl-diphenylsilyl, tert-butyl-dimethylsilyl, trimethylsilyl,tri-iso-propylsilyl, tert-butyldimethylsilyloxymethyl,0-methoxyethoxymethyl, [bis-(4-methoxyphenyl)phenylmethyl)],methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl,ethoxyethyl, triphenylmethyl, —C(O)R⁵⁶, —C(O)OR⁵⁷, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, —(C₂-C₆) alkynyl, aryl, and heteroaryl, each alkyl,alkynyl, alkenyl, aryl, and heteroaryl being unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups. EachR⁵⁶ and each R⁵⁷ can be independently selected from —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, —(C₂-C₆) alkynyl, aryl, and heteroaryl, each beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups.

R⁸ is —OR⁵¹, —F, —Cl, —Br, —I, phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is—(C₁-C₆) alkyl or an oxygen protecting group. In certain embodiments,R¹⁷ is selected from the group consisting of methyl, ethyl, iso-butyl,acetyl, benzyl, benzoyl, allyl, allyloxycarbonyl, phenyl,phenyloxycarbonyl, and alkyloxycarbonyl.

In certain embodiments of these methods for making compounds of formula(74) and formula (75), R^(59′) is —OR¹⁷ and R¹⁷ is —C(O)OR⁵⁷. Inparticular embodiments of these methods, R⁵⁷ is iso-butyl. In anotherparticular embodiment, R⁵⁷ is ethyl. In a specific embodiment, R⁵⁷ isallyl. In another embodiment, R⁵⁴ is —OCH₃.

In certain embodiments of these methods for making compounds of formula(74) and formula (75), step (a) in each instance can be carried out inthe presence of an iodide salt. In certain embodiments, the iodide saltis present in a sub-stoichiometric amount. In certain embodiments, theiodide salt is present in a catalytic amount. The iodide salt can beselected from the group consisting of NaI, KI, LiI, CsI, RuI, MgI₂,CaI₂, NH₄I, tetrabutylammonium iodide, and combinations of two or morethereof. In particular embodiments, the iodide salt is NaI.

In certain embodiments of these methods for making compounds of formula(74) and formula (75), step (c) in each instance can be carried out inthe presence of an iodide salt. In certain embodiments, the iodide saltis present in a sub-stoichiometric amount. In certain embodiments, theiodide salt is present in a catalytic amount. The iodide salt can beselected from the group consisting of NaI, KI, LiI, CsI, RuI, MgI₂,CaI₂, NH₄I, tetrabutylammonium iodide, and combinations of two or morethereof. In particular embodiments, the iodide salt is NaI.

In another embodiment, the compound of formula (77)

is converted to a compound of formula (83)

by contacting the compound of formula (77) with a transition metalcatalyst. This decarboxylation reaction corresponds to that depicted inStep 2 of Scheme 1, as well as the reaction depicted in Schemes 3, 7,and 9 above, and suitable conditions for this reaction are analogous toor readily adapted from those of Example 4 and Example 5.

In another embodiment, the compound of formula (81)

is converted to a compound of formula (84)

by contacting the compound of formula (81) with a transition metalcatalyst. This decarboxylation reaction corresponds to that depicted inStep 2 of Scheme 1, as well as the reaction depicted in Schemes 3, 7,and 9 above, and suitable conditions for this reaction are analogous toor readily adapted from those of Example 4 and Example 5.

In another embodiment, the present disclosure provides a method formaking a compound of formula (88)

comprising

(a) contacting a compound of formula (76)

with a compound of formula (85)

in a solvent to provide a compound of formula (86)

(b) optionally, converting a carbonate group at R^(59′) to an —OH groupto provide a compound of formula (100)

(c) decarboxylating the compound of formula (86) or the compound offormula (100) to provide a compound of formula (87)

and

(d) hydrogenating the compound of formula (87) to provide the compoundof formula (88).

In a further embodiment, the present disclosure provides a method formaking a compound of formula (89)

comprising

(a) contacting a compound of formula (80)

with a compound of formula (85)

in a solvent to provide a compound of formula (90)

(b) optionally, converting a carbonate group at R^(59′) to an —OH groupto provide a compound of formula (101)

(c) decarboxylating the compound of formula (90) or a compound offormula (101) to provide a compound of formula (91) and

(d) hydrogenating the compound of formula (91) to provide the compoundof formula (89).

The methods disclosed above for conversion of compounds of formula (76)to compounds of formula (88) (via intermediates of formula (86) andformula (87)) and for conversion of compounds of formula (80) tocompounds of formula (89) (via intermediates of formula (90) and formula(91)) are analogous to Steps 3-5 of Scheme 16.

In another embodiment, the compounds of formula (88) are prepared bycontacting a compound of formula (76) with a compound selected from thegroup consisting of compound (119), a compound of formula (19), acompound of formula (29), and a compound of formula (67), to provide acarbamate intermediate that can be decarboxylated and then hydrogenatedto provide the compound of formula (88), using methods and reagentsdisclosed herein.

In a further embodiment, the compounds of formula (89) are prepared bycontacting a compound of formula (80) with a compound selected from thegroup consisting of compound (119), a compound of formula (19), acompound of formula (29), and a compound of formula (67), to provide acarbamate intermediate that can be decarboxylated and then hydrogenatedto provide the compound of formula (89), using methods and reagentsdisclosed herein.

4.27 Processes Comprising Transition Metal-Catalyzed Decarboxylation ofCompounds Derived from Thebaine, Morphine, and Codeine

The present disclosure provides illustrative processes comprisingtransition metal-catalyzed reactions that are useful for the conversionof oripavine to naloxone (Schemes 6 and 10), to noroxymorphone (Schemes6 and 10 combined with Scheme 14), and to naltrexone (Scheme 16). Inother embodiments, the reactions, processes, and reagents disclosedherein can also be used for the synthesis of clinically and commerciallyimportant derivatives of thebaine, morphine, and codeine. The followingsections disclose the preparation of an illustrative compound,naltrexone, from morphine, codeine, and thebaine, using processes thatincorporate N-allyl decarboxylation reactions disclosed herein. Knownprocesses for the preparation of, e.g., buprenorphine, naloxone,nalorphine, nalmefene, nalbuphine, noroxymorphone, and noroxycodone frommorphine, codeine, and thebaine, can be adapted in a similar manner toincorporate N-allyl decarboxylation reactions disclosed herein toprovide improved methods for the production of those compounds.

4.27.1 Preparation of Naltrexone from Morphine

U.S. Pat. No. 5,952,495 provides two alternate methods that could beused for the preparation of naltrexone. In the first morphine isconverted, in two steps, to 6-acetyl-3-benzylmorphine which isN-demethylated by reaction with either 1-chloroethyl chloroformate orcyanogen bromide followed by acid hydrolysis to 3-benzylnormorphine.Reaction of 3-benzylnormorphine with a benzyl halide provides3,17-dibenzylnormorphine, which is oxidized to3,17-dibenzylnormorphinone by Swern oxidation. The3,17-dibenzylnormorphinone, in turn, is oxidized to3,17-dibenzyl-14-hydroxynormorphinone by either (1) directly reactingwith hydrogen peroxide in formic acid or (2) first converting to3,17-dibenzylnormorphinone dienol acylate and then reacting the latterwith hydrogen peroxide in formic acid or a peroxyacid. The oxidizedproduct is then hydrogenated to produce noroxymorphone. Reaction ofnoroxymorphone with, e.g., cyclopropyl methyl bromide, would providenaltrexone. This process therefore includes either eight or nine stepsdepending on the route taken for introduction of the 14-hydroxyl group.

In the second approach, morphine is converted to 3-benzylnormorphine,which is reacted with cyclopropylmethyl halide to produce3-benzyl-17-cyclopropylmethylnormorphine which, in turn, is oxidized to3-benzyl-17-cyclopropylmethyl-normorphinone by Swern oxidation. Thiscompound is oxidized to3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone by either (1)directly reacting with hydrogen peroxide in formic acid or (2) firstconverting to 3-benzyl-17-cyclopropylmethylnormorphinone dienol acylateand then reacting the latter with hydrogen peroxide in formic acid or aperoxyacid. The oxidized product,3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone, is hydrogenatedto remove the benzyl group and reduce the 7,8-double bond simultaneouslyto provide naltrexone.

Both of the processes of U.S. Pat. No. 5,952,495 describing thepreparation of naltrexone from morphine include either eight or ninesteps depending on the route taken for introduction of the 14-hydroxylgroup.

In contrast, naltrexone can be prepared from morphine in five or fewersteps according to methods disclosed herein, e.g., as depicted in Scheme31.

As indicated in Scheme 31, the 3- and 6-hydroxyl of morphine can beconverted to the bis-cycloprop-1-en-1-ylmethyl carbonate derivativeduring the depicted N-demethylation reaction withcycloprop-1-en-1-ylmethyl chloroformate. In Step 2, the carbonate groupscan be removed while the carbamate can be converted to theN-cyclopropenylmethyl derivative in Step 3 using the transitionmetal-catalyzed decarboxylation reactions disclosed herein. Conversionof the 6-hydroxyl group to a keto moiety (Step 4) and introduction ofthe 14-hydroxyl group and hydrogenation of the indicated double bonds(Step 5) can be carried out using methods disclosed herein or usingthose disclosed, e.g., in U.S. Pat. No. 5,952,495. Alternatively, theprocess of Scheme 31 could further modified by utilizing protectinggroups for the 3- and 6-hydroxyl groups and, subsequently, hydrolyzingthose protecting groups either before or after the transitionmetal-catalyzed decarboxylation reactions, as depicted in Scheme 32.

As indicated in Scheme 32, the 3- and 6-hydroxyl of morphine can beprotected with a suitable oxygen protecting group (Step 1) beforeN-demethylation with cycloprop-1-en-1-ylmethyl chloroformate (Step 2).In one route, the protecting groups are removed (Step 3A) beforeconversion of the carbamate to the N-cyclopropenylmethyl derivative(Step 4A) using the transition metal-catalyzed decarboxylation reactionsdisclosed herein. Alternatively, the transition metal decarboxylation(Step 3B) can be carried out before removal of the protecting groups(Step 4B). Conversion of the 6-hydroxyl group to a keto moiety,introduction of the 14-hydroxyl group, and hydrogenation of theindicated double bonds can be carried out using methods disclosed hereinor using those disclosed, e.g., in U.S. Pat. No. 5,952,495. In anotheralternative embodiment, the oxygen protecting group is selected fromamong those removed during the hydrogenation reaction (e.g., R isbenzyl), thereby obviating the need for Step 4B.

4.27.2 Preparation of Naltrexone from Codeine

Schwartz (Schwartz et al. (1981) J. Med. Chem. (1981) 24:1525-1528)describe a set of reactions that could be used to convert codeine tonaltrexone in eight steps. According to this method, codeine isN-demethylated with ethyl chloroformate and then oxidized with manganesedioxide to provide N-(ethoxycarbonyl)norcodeinone which, upon treatmentwith sodium acetate in acetic anhydride, provides a dienol acetatederivative. Oxidation of that compound with singlet oxygen provided thecorresponding 14-hydroxy product. Hydrogenation of the 7,8-double bond,hydrolysis of the N-ethyloxycarbonyl moiety followed by alkylation withcyclopropyl methyl bromide, and conversion of the 3-methoxy group to ahydroxyl group with boron tribromide would complete the conversion ofcodeine to naltrexone.

As indicated in Step 1 in Scheme 33, codeine is oxidized to provide the6-keto derivative, which is converted to the correspondingN-cyclopropylmethyl compound in Steps 2 and 3 using the transitionmetal-catalyzed decarboxylation reactions disclosed herein. TheN-cyclopropylmethyl is oxidized to include the 14-hydroxyl group (e.g.,by reaction with hydrogen peroxide in formic acid as disclosed in U.S.Pat. No. 5,952,495). Hydrogenation of the double bonds and conversion ofthe 3-methoxy group to a 3-hydroxyl by known methods completes theprocess of Scheme 33, providing naltrexone from codeine in six steps.

4.27.3 Preparation of Naltrexone from Thebaine

The disclosure of GB 939287 can be used to provide a seven step processfor conversion of thebaine to naltrexone. In this process, thebaine isoxidized to 14-hydroxycodeinone, which is hydrogenated to oxycodone. The14-hydroxyl group of oxycodone is first acetylated and thethus-protected compound first reacted with cyanogen bromide and thenhydrolyzed to noroxycodone. Alkylation with cyclopropylmethyl bromideand conversion of the methoxy group to a hydroxyl moiety provides thefinal product, naltrexone. U.S. Pat. Nos. 4,639,520 and 4,472,253 and WO98/02033 A1 also can be used to provide a seven step process forconversion of thebaine to naltrexone that differs from that of the GB939287 patent with respect to the order in which the reactions arecarried out.

In contrast, naltrexone can be prepared from thebaine in five stepsaccording to methods disclosed herein, e.g., as depicted in Scheme 34.

As indicated in Scheme 34, thebaine can be oxidized to introduce the14-hydroxyl moiety (Step 1), and the N-methyl group replaced with acyclopropyl methyl in Steps 2-4, including the transitionmetal-catalyzed decarboxylation reaction of Step 3 according to themethods disclosed herein. Conversion of the 3-methoxy group to a3-hydroxyl by known methods completes the process of Scheme 34,providing naltrexone from thebaine in five steps.

4.28 Compositions

The present disclosure also provides a composition comprising a compoundof formula (42)

and a transition metal catalyst, where R¹⁴ and R¹⁶ are eachindependently selected from —OH, —H, and —OR¹⁷; R¹⁵ is selected from—OH, —H, —OR¹⁷, ═O, and ═CH₂; and R¹⁷ is an oxygen protecting group.

In another embodiment, the present disclosure provides a compositionprepared by admixing a compound of formula (42)

and a transition metal catalyst, where R¹⁴ and R¹⁶ are eachindependently selected from —OH, —H, and —OR¹⁷; R¹⁵ is selected from—OH, —H, —OR¹⁷, ═O, and ═CH₂; and R¹⁷ is an oxygen protecting group.

In another embodiment, the present disclosure provides a method forpreparing a composition containing a compound of formula (42) comprisingadmixing the compound of formula (42)

and a transition metal catalyst, where R¹⁴ and R¹⁶ are eachindependently selected from —OH, —H, and, —oR¹⁷, R¹⁵ is selected from—OH, —H, —OR¹⁷, ═O, and ═CH₂; and R¹⁷ is an oxygen protecting group.

In another embodiment, the present disclosure provides a compositioncomprising a tertiary alcohol and a compound of formula (93)

where R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R⁶ and R⁷ are taken together withthe carbon atoms to which each is bound to form a carbocyclic ring of 3,4, 5, 6, 7, 8, or 9 carbon atoms, the carbocyclic ring beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; each R⁸ is independently selected from—OR⁵¹, —F, —Cl, —Br, —I, phenyl, and —(C₁-C₆) alkyl; each R⁵¹ isindependently selected from —(C₁-C₆) alkyl and an oxygen protectinggroup; and X is selected from —Cl, —Br, and —I. In certain embodiments,R⁶ and R⁷ are taken together with the carbon atoms to which each isbound to form a carbocyclic ring of 3, 4, 5, or 6 carbon atoms, thecarbocyclic ring being unsubstituted or substituted with 1, 2, 3, 4, or5 independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I,phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is —(C₁-C₆) alkyl or an oxygenprotecting group.

In another embodiment, the present disclosure provides a compositioncomprising a tertiary alcohol and a compound of formula (6)

where one of Y and Y′ is a leaving group and the other is —H; R⁴ isselected from the group consisting of —H, —(C₁-C₆) alkyl, phenyl, allyl,-2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl, -2-butynyl,-3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R⁶ and R⁷ are taken together withthe carbon atoms to which each is bound to form a carbocyclic ring of 3,4, 5, 6, 7, 8, or 9 carbon atoms, the carbocyclic ring beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; each R⁸ is independently selected from—OR⁵¹, —F, —Cl, —Br, —I, phenyl, and —(C₁-C₆) alkyl; each R⁵¹ isindependently selected from —(C₁-C₆) alkyl and an oxygen protectinggroup; and X is selected from —Cl, —Br, and —I. In certain embodiments,R⁶ and R⁷ are taken together with the carbon atoms to which each isbound to form a carbocyclic ring of 3, 4, 5, or 6 carbon atoms, thecarbocyclic ring being unsubstituted or substituted with 1, 2, 3, 4, or5 independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F, —Cl, —Br, —I,phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is —(C₁-C₆) alkyl or an oxygenprotecting group.

In another embodiment, the present disclosure provides a compositioncomprising a tertiary alcohol and a compound of formula (8)

where R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R⁶ and R⁷ are taken together withthe carbon atoms to which each is bound to form a carbocyclic ring of 3,4, 5, 6, 7, 8, or 9 carbon atoms, the carbocyclic ring beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; each R⁸ is independently selected from—OR⁵¹, —F, —Cl, —Br, —I, phenyl, and —(C₁-C₆) alkyl; each R⁵¹ isindependently selected from —(C₁-C₆) alkyl and an oxygen protectinggroup; and X, Z, and Z′ are each independently selected from —Cl, —Br,and —I. In certain embodiments, R⁶ and R⁷ are taken together with thecarbon atoms to which each is bound to form a carbocyclic ring of 3, 4,5, or 6 carbon atoms, the carbocyclic ring being unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups; R⁸is —OR⁵¹, —F, —Cl, —Br, —I, phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is—(C₁-C₆) alkyl or an oxygen protecting group.

In another embodiment, the present disclosure provides a compositioncomprising a tertiary alcohol and a compound of formula (13)

where R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

R⁵ is selected from —H, —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆)alkynyl, each alkyl, alkenyl, and alkynyl being unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups; eachR⁸ is independently selected from —OR⁵¹, —F, —Cl, —Br, —I, phenyl, and—(C₁-C₆) alkyl; each R⁵¹ is independently selected from —(C₁-C₆) alkyland an oxygen protecting group; and X is selected from —Cl, —Br, and —I.

In another embodiment, the present disclosure provides a compositioncomprising a tertiary alcohol and a compound of formula (19)

where R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

R⁵ is selected from —H, —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆)alkynyl, each alkyl, alkenyl, and alkynyl being unsubstituted orsubstituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups; eachR⁸ is independently selected from —OR⁵¹, —F, —Cl, —Br, —I, phenyl, and—(C₁-C₆) alkyl; each R⁵¹ is independently selected from —(C₁-C₆) alkyland an oxygen protecting group; p is an integer selected from 1, 2, 3,and 4; and X is selected from —Cl, —Br, and —I.

In another embodiment, the present disclosure provides a compositioncomprising a tertiary alcohol and a compound of formula (23)

where R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl,—(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynylbeing unsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups, or R⁶ and R⁷ are taken together withthe carbon atoms to which each is bound to form a carbocyclic ring of 3,4, 5, 6, 7, 8, or 9 carbon atoms, the carbocyclic ring beingunsubstituted or substituted with 1, 2, 3, 4, or 5independently-selected R⁸ groups; each R⁸ is independently selected from—OR⁵¹, —F, —Cl, —Br, —I, phenyl, and —(C₁-C₆) alkyl; each R⁵¹ isindependently selected from —(C₁-C₆) alkyl and an oxygen protectinggroup; V is a leaving group; and X is selected from —Cl, —Br, and —I. Incertain embodiments, R⁶ and R⁷ are taken together with the carbon atomsto which each is bound to form a carbocyclic ring of 3, 4, 5, or 6carbon atoms, the carbocyclic ring being unsubstituted or substitutedwith 1, 2, 3, 4, or 5 independently-selected R⁸ groups; R⁸ is —OR⁵¹, —F,—Cl, —Br, —I, phenyl, or —(C₁-C₆) alkyl; and R⁵¹ is —(C₁-C₆) alkyl or anoxygen protecting group.

In another embodiment, the present disclosure provides a compositioncomprising a tertiary alcohol and a compound of formula (29)

where R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl,phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl,-2-butynyl, -3-butynyl, -2-pentynyl,

and each X is independently selected from —Cl, —Br, and —I.

In another embodiment, the present disclosure provides a compositioncomprising a tertiary alcohol and a compound of formula (46)

where Y is a leaving group; and X is selected from —Cl, —Br, and —I.

In each of the compositions in Section 4.28 containing a tertiaryalcohol, in one embodiment the tertiary alcohol is a compound of formula(4)

where R⁶, R⁷, and R⁸ are each independently —(C₁-C₆) alkyl. In anotherembodiment, the tertiary alcohol is selected from the group consistingof tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol,2,3-dimethyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-hexanol, andcombinations of two or more thereof. In another embodiment, the tertiaryalcohol is tert-amyl alcohol.

In each of the compositions in Section 4.28 containing a tertiaryalcohol, in one embodiment the composition can further comprise aniodide salt. In certain embodiments, the iodide salt is present in asub-stoichiometric amount. In certain embodiments, the iodide salt ispresent in a catalytic amount. In another embodiment, the iodide salt isselected from the group consisting of NaI, KI, LH, CsI, RuI, MgI₂, CaI₂,NH₄I, tetrabutylammonium iodide, and combinations of two or morethereof. In another embodiment, the iodide salt is NaI.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, that would be within the purview of those skilled inthe art, and changes in formulation or changes in experimental design,are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES

The reactions and processes of the present disclosure are described inmore detail below.

Example 1 N-Demethylation of Oxycodone

Into a round bottom flask equipped with a stir bar was charged oxycodone(3.15 g, 9.99 mmol), potassium carbonate (2.07 g, 15.0 mmol),dichloromethane (31.5 mL), and 1,2-dichloroethane (15 mL). The flask wasequipped with a reflux condenser and the mixture was allowed to stir ata temperature of about 20° C. under an atmosphere of nitrogen. Into themixture was added a first portion of allyl chloroformate (6.35 mL, 59.95mmol) drop-wise over 5 minutes. The resulting reaction mixture washeated to reflux at 52.5° C. and allowed to stir at that temperature for16 hours. Thereafter, the reaction mixture was sampled and analyzed byHPLC; approximately 32% of the starting oxycodone was determined toremain.

Into the mixture was added a second and final portion (3.2 mL, 30.21mmol) of allyl chloroformate and an additional 16.5 mL of1,2-dichloroethane. The resulting reaction mixture was heated to refluxat 57.5° C. and allowed to stir for an additional 24 hours. Thereafter,the reaction mixture was sampled and analyzed by HPLC; approximately 22%of oxycodone was determined to remain.

The mixture was cooled to a temperature of about 20° C. and filteredthrough a pad of CELITE to remove residual solids. The filtrate wasconcentrated under reduced pressure. The resulting material wasdissolved in a mixture of ethyl acetate (150 mL) and 0.5N aqueoushydrochloric acid (120 mL). The layers were separated and the organiclayer was washed with water (100 mL). The organic layer was concentratedunder reduced pressure to provide a 2:1 mixture of17-allyloxycarbonyl-noroxycodone:14,17-di-allyloxycarbonyl-noroxycodoneas a yellow oil (1.98 g, 4.79 mmol).

Example 2 N-Demethylation of Oxymorphone

Into a round bottom flask equipped with a stir bar was chargedoxymorphone (6.02 g, 19.96 mmol), potassium carbonate (4.15 g, 30.03mmol), and 1,2-dichloroethane (60 mL). The flask was equipped with areflux condenser and the mixture was allowed to stir at a temperature ofabout 20° C. under an atmosphere of nitrogen. Into the mixture was addeda first portion of allyl chloroformate (12.7 mL, 119.91 mmol) drop-wiseover 10 minutes. The resulting reaction mixture was heated to reflux at81.5° C. and allowed to stir at that temperature for 18 hours.Thereafter, the reaction mixture was sampled and analyzed by HPLC;approximately 24% of 3-allyloxycarbonyl oxymorphone was determined to bepresent. As noted above, at initial time points the major productobserved was 3-allyloxycarbonyl-oxymorphone.

Into the mixture was added a second and final portion (4.2 mL, 39.65mmol) of allyl chloroformate and an additional 2.07 g (14.98 mmol) ofpotassium carbonate. The resulting reaction mixture was allowed to stirfor an additional 24 hours at reflux. Thereafter, the reaction mixturewas sampled and analyzed by HPLC; approximately 18% of3-allyloxycarbonyl oxymorphone was determined to be present.

The mixture was cooled to a temperature of about 20° C. and filteredthrough a pad of CELITE to remove residual solids. The filtrate wasconcentrated under reduced pressure. The resulting material wasdissolved in a mixture of ethyl acetate (200 mL) and 0.5N aqueoushydrochloric acid (150 mL). The organic layer was dried with sodiumsulfate, filtered, and concentrated under reduced pressure to provide a3:1 mixture of3,17-di-allyloxycarbonyl-noroxymorphone:3,14,17-tri-allyloxycarbonyl-noroxymorphoneas a yellow oil (5.64 g, 12.38 mmol).

Example 3 N-Demethylation of Oxymorphone

Into a round bottom flask equipped with a stir bar was chargedoxymorphone (10.06 g, 33.38 mmol), sodium bicarbonate (8.46 g, 100.70mmol), and tert-amyl alcohol (70 mL). The flask was equipped with aDean-Stark trap and condenser. The mixture was allowed to stir at atemperature of about 20° C. for 5 minutes. Into the mixture was added afirst portion of allyl chloroformate (3.90 mL, 36.69 mmol) drop-wiseover 5 minutes. The resulting reaction mixture was heated to 55° C. andallowed to stir at that temperature for 1 hour. Thereafter, the reactionmixture was sampled and analyzed by HPLC; the conversion to3-allyloxycarbonyl-oxymorphone was determined to be greater than 99%.The reaction mixture was heated to 105° C. and 25 mL of reaction solventwas removed from the round bottom flask by distillation into theDean-Stark trap.

The mixture was cooled to 85° C. Into the mixture was added a secondportion of allyl chloroformate (8.90 mL, 83.73 mmol). The resultingreaction mixture was allowed to stir at 85° C. for 6 hours and thencooled to a temperature of about 20° C. and stirred at that temperaturefor 16 hours. Thereafter, the reaction mixture was sampled and analyzedby HPLC; approximately 42% of 3-allyloxycarbonyl-oxymorphone wasdetermined to remain. The 25 mL of liquid in the Dean-Stark trap wasemptied and an additional 30 mL of tert-amyl alcohol was added to themixture. The resulting reaction mixture was heated to 105° C. and 25 mLof reaction solvent was removed from the round bottom flask bydistillation into the Dean-Stark trap.

The mixture was cooled to 85° C. and a third portion of allylchloroformate (3.90 mL, 36.69 mmol) was added. The resulting reactionmixture was allowed to stir at 85° C. for 6 hours and then cooled to atemperature of about 20° C. and stirred at that temperature for 16hours. Thereafter, the reaction mixture was sampled and analyzed byHPLC; approximately 28% of 3-allyloxycarbonyl-oxymorphone was determinedto remain.

The 25 mL of liquid in the Dean-Stark trap was emptied and an additional20 mL of tert-amyl alcohol was added to the mixture. The resultingreaction mixture was heated to 105° C. and 25 mL of reaction solvent wasremoved from the round bottom flask by distillation into the Dean-Starktrap.

The mixture was cooled to 85° C. and a fourth portion of allylchloroformate (3.90 mL, 36.69 mmol) was added. The resulting reactionmixture was allowed to stir at 85° C. for 6 hours and then cooled to atemperature of about 20° C. and stirred at that temperature for 16hours. Thereafter, the reaction mixture was sampled and analyzed byHPLC; approximately 7% of 3-allyloxycarbonyl-oxymorphone was determinedto remain. The 25 mL of liquid in the Dean-Stark trap was emptied and anadditional 25 mL of tert-amyl alcohol was added to the mixture. Theresulting reaction mixture was heated to 105° C. and 25 mL of reactionsolvent was removed from the round bottom flask by distillation into theDean-Stark trap.

The mixture was cooled to 85° C. and a fifth and final portion of allylchloroformate (3.90 mL, 36.69 mmol) was added. The resulting reactionmixture was allowed to stir at 85° C. for 6 hours and then cooled to atemperature of about 20° C. and stirred at that temperature for 16hours. Thereafter, the reaction mixture was sampled and analyzed byHPLC; approximately 0.6% of 3-allyloxycarbonyl-oxymorphone wasdetermined to remain. HPLC analysis also demonstrated that a 6.3:1mixture of3,17-di-allyloxycarbonyl-noroxymorphone:3,14,17-tri-allyloxycarbonyl-noroxymorphonewas prepared.

To the reaction mixture was added sodium carbonate (4.74 g, 44.72 mmol)and water (35 mL). The reaction mixture was heated to 90° C. and allowedto stir at that temperature for 17 hours. The reaction mixture wascooled to a temperature of about 20° C. and sampled for HPLC analysis;the results demonstrated that greater than 99% conversion to17-allyloxycarbonyl-noroxymorphone was achieved. The reaction mixturewas acidified to a pH of 1.5 with concentrated hydrochloric acid (10 mL)and the mixture was allowed to stir for 10 minutes. Mixing was stoppedand the layers were allowed to separate. The organic layer was separatedand washed twice with 10% aqueous sodium hydrogen sulfate (50 mL foreach wash). The organic layer was concentrated under reduced pressure toprovide crude 17-allyloxycarbonyl-noroxymorphone as a yellow form (8.85g, 23.83 mmol).

Example 4 Decarboxylative Allylation of 17-Allyloxycarbonyl-Noroxycodoneand 14,17-Di-Allyloxycarboynly-Noroxycodone

Into a round bottom flask equipped with a stir bar was dissolved a 2:1mixture of17-allyloxycarbonyl-noroxycodone:14,17-di-allyloxycarbonyl-noroxycodone(264 mg, 0.67 mmol) in dichloromethane (5 mL). The mixture was allowedto stir at a temperature of about 20° C. for 10 minutes. To the mixturewas added tetrakis(triphenylphosphine)palladium[0] (40 mg, 0.035 mmol).The resulting reaction mixture was allowed to stir at a temperature ofabout 20° C. for 3 hours before being filtered through a pad of CELITE.The filtrate was concentrated under reduced pressure. The resulting oilwas dissolved in ethyl acetate (20 mL) and the product was extractedwith 0.5N aqueous hydrochloric acid (100 mL). The aqueous layer wasbasified to a pH of 10.2 with 50% sodium hydroxide and extracted threetimes with dichloromethane (150 mL for each extraction). The combinedorganic portions were dried with sodium sulfate, filtered, andconcentrated under reduced pressure to provide N-allyl-oxycodone as ayellow oil (183 mg, 0.54 mmol).

Example 5 Decarboxylative Allylation of3,17-Di-Allyloxycarbonyl-Noroxymorpone:3,14,17-Tri-Allyloxycarbonyl-Noroxymorphone

Into a round bottom flask equipped with a stir bar was dissolved a 3:1mixture of3,17-di-allyloxycarbonyl-noroxymorphone:3,14,17-tri-allyloxycarbonyl-noroxymorphone(1.41 g, 2.98 mmol) in chloroform (10 mL). The mixture was allowed tostir at a temperature of about 20° C. for 10 minutes. To the mixture wasadded tetrakis(triphenylphosphine)palladium[0] (180 mg, 0.155 mmol). Theresulting reaction mixture was allowed to stir at a temperature of about20° C. for 4 hours before being filtered through a pad of CELITE. Thefiltrate was concentrated under reduced pressure. The resulting oil wasdissolved in ethyl acetate (100 mL) and the product was extracted with0.5N aqueous hydrochloric acid (100 mL). The aqueous layer was washedtwice with ethyl acetate (100 mL for each wash). The aqueous layer wasbasified to a pH of 9.5 with 50% sodium hydroxide and extracted threetimes with chloroform (100 mL for each extraction). The organic portionswere combined, dried with sodium sulfate, filtered, and concentratedunder reduced pressure to provide 3-allyl-naloxone as a yellow oil,contaminated with approximately 25% of triphenylphosphine (1.41 g of oilcontaining about 1.05 g of 3-allyl-naloxone (about 2.88 mmol)).

Example 6 O-De-Allylation of 3-Allyl-Naloxone

Into a round bottom flask equipped with a stir bar was dissolved3-allyl-naloxone (0.28 g, 0.76 mmol) in methanol (10 mL). To the mixturewas added potassium carbonate (0.40 g, 2.89 mmol) andtetrakis(triphenylphosphine)palladium[0] (0.0215 g, 0.019 mmol). Theresulting reaction mixture was allowed to stir at a temperature of about20° C. for 4 hours. Thereafter, the reaction mixture was sampled andanalyzed by HPLC; the results demonstrated that greater than 99%conversion to naloxone was achieved. The mixture was filtered through apad of CELITE and the filtrate was concentrated under reduced pressure.The resulting oil was dissolved in ethyl acetate (50 mL) and extractedwith 0.5N aqueous hydrochloric acid (75 mL). The aqueous layer waswashed twice with ethyl acetate (50 mL for each wash). The aqueous layerwas basified to a pH of 9.0 with 50% sodium hydroxide and extractedthree times with chloroform (50 mL for each extraction). The organicportions were combined, dried with sodium sulfate, filtered, andconcentrated under reduced pressure to provide naloxone as a yellow oil(0.23 g, 0.70 mmol).

Example 7 N-De-Allylation of Naloxone

Into a 5 L reactor equipped with an overhead stirrer and refluxcondenser was dissolved N,N-dimethyl barbituric acid (32.56 g, 208.5mmol) and tetrakis(triphenylphosphine)palladium[0] (20.36 g, 17.6 mmol)in dichloromethane (1.5 L). The mixture was stirred at a temperature ofabout 20° C. Into the mixture was charged naloxone (110.90 g, 338.8mmol) as a suspension in dichloromethane (1 L). The resulting reactionmixture was stirred at 38° C. for 16 hours. The mixture was cooled to atemperature of about 20° C. and the solids were filtered off underreduced pressure. The solids were washed with dichloromethane (5 L)followed by washing with water (2.5 L). The solids were dissolved into a10:1 mixture of water:concentrated sulfuric acid at 40° C. The heatedaqueous solution was washed with dichloromethane (0.5 L) and thenbasified to a pH of 9.05 with 28% ammonium hydroxide. The resultingsolids were filtered and dried under reduced pressure at 100° C. for 20hours to provide noroxymorphone as a white solid (87.12 g, 303.2 mmol).

Example 8 Allylation of Noroxymorphone with Allyl Acetate

Into a round bottom flask equipped with a stir bar was chargednoroxymorphone (2.89 g, 10.1 mmol), triethylamine (4.20 mL, 30.1 mmol),toluene (50 mL), tetrakis(triphenylphosphine)palladium[0] (1.15 g, 1.00mmol), and allyl acetate (1.40 mL, 12.9 mmol). The flask was equippedwith a reflux condenser and the resulting reaction mixture was stirredand heated at 80° C. for 64 hours. The mixture was cooled to atemperature of about 20° C. and filtered through a plug of CELITE. Thefiltrate was concentrated under reduced pressure. The concentratedmaterial was dissolved in a mixture of ethyl acetate (150 mL) and 0.75Naqueous hydrochloric acid (100 mL) and allowed to stir at a temperatureof about 20° C. for 20 minutes. The layers were separated and theaqueous layer was washed with an additional 150 mL of ethyl acetate. Theaqueous layer was basified to a pH of 9.05 with 28% ammonium hydroxideand extracted twice with dichloromethane (100 mL for each extraction).The organic portions were combined and concentrated under reducedpressure. Naloxone (HPLC purity of 76%) was isolated as an oil,contaminated with triphenylphosphine and 3-allyl-naloxone (isolated 2.78g crude of 76% purity containing about 6.37 mmol of naloxone)).

Example 9 Allylation of Noroxymorphone with N-Allyl-Dimethylamine

Into a round bottom flask equipped with a stir bar was charged1,4-bis(diphenylphosphino)-butane (0.352 g, 0.82 mmol), palladium(II)acetate (0.10 g, 0.44 mmol), and DMF (10 mL). The flask was sealed andstirred at a temperature of about 20° C. for 15 minutes. Thereafter,into the flask was added N-allyl-dimethylamine (1.45 mL, 12.2 mmol),followed by noroxymorphone (2.85 g, 9.92 mmol) as a slurry in DMF (30mL) and acetic acid (1.20 mL, 21.0 mmol). The flask was equipped with areflux condenser and the resulting reaction mixture was stirred andheated at 50° C. for 16 hours. Thereafter, the reaction mixture wassampled and analyzed by HPLC; conversion to naloxone was determined tobe low, no more than approximately 1-2%.

Example 10 N-Demethylation of N-Methylmorpholine

Into a round bottom flask equipped with a stir bar was chargedN-methylmorpholine (2.50 mL, 22.7 mmol), 1,2-dichloroethane (35 mL), andpotassium carbonate (4.75 g, 34.4 mmol). The flask was equipped with areflux condenser and the mixture was allowed to stir at a temperature ofabout 20° C. under an atmosphere of nitrogen. Into the mixture was addeda first portion of allyl chloroformate (5.00 mL, 47.2 mmol) drop-wiseover 5 minutes. The resulting reaction mixture was heated to 85° C. andallowed to stir at that temperature for 16 hours. Thereafter, a sampleof the reaction material was removed, concentrated under reducedpressure, and analyzed by ¹H NMR; conversion to the carbamate wasdetermined to be 55%.

Into the mixture was added a second and final portion of (5.00 mL, 47.2mmol) of allyl chloroformate and the resulting reaction mixture wasallowed to stir at 85° C. for an additional 6 hours. The reactionmixture was cooled to a temperature of about 20° C. and filtered througha plug of CELITE. The filtrate was concentrated under reduced pressureand analyzed by ¹H NMR; greater than 95% conversion to4-allyloxycarbonyl-morpholine was achieved.

Example 11 Decarboxylative Allylation of 4-Allyloxycarbonyl-Morpholine

Into a round bottom flask equipped with a stir bar was charged4-allyloxycarbonyl-morpholine (373 mg, 2.18 mmol) and dichloromethane(3.7 mL). The mixture was allowed to stir at a temperature of about 20°C. for 5 minutes. To the mixture was addedtetrakis(triphenylphosphine)palladium[0] (50 mg, 0.043 mmol). Theresulting reaction mixture was allowed to stir at a temperature of about20° C. for 3 hours before being filtered through a pad of CELITE. Thefiltrate was concentrated under reduced pressure. The resulting oil wasanalyzed by ¹H NMR; greater than 95% conversion to N-allyl-morpholinewas achieved.

Example 12 Dehalogenation of 3-Chloropropyl Morpholine-4-Carboxylate

Into a round bottom flask equipped with a stir bar was charged3-chloropropyl morpholine-4-carboxylate (2.06 g, 9.92 mmol), 50% sodiumhydroxide (5.5 mL), 40% tetrabutyl ammonium hydroxide (2.5 mL, 3.75mmol), sodium iodide (0.18 g, 1.20 mmol), tert-butyl methyl ether (12.5mL), and water (4.5 mL). The resulting reaction mixture was allowed tostir at a temperature of about 20° C. for 24 hours. The mixture wasdiluted with ethyl acetate (50 mL) and water (50 mL). The organic layerwas separated and concentrated under reduced pressure. The resulting oilwas analyzed by ¹H NMR; greater than 95% conversion to4-allyloxycarbonyl-morpholine was achieved.

Example 13 N-De-Ethylation of N,N-Di-Iso-Propylethylamine

Into a round bottom flask equipped with a stir bar and reflux condenserwas charged N,N-di-iso-propylethylamine (3.75 mL, 21.5 mmol), a firstportion of allyl chloroformate (3.30 mL, 31.2 mmol), and toluene (15.0mL). The resulting reaction mixture was heated to 110° C. and allowed tostir at that temperature for 20 hours. Thereafter, the reaction mixturewas sampled and analyzed by HPLC; the results demonstrated that greaterthan 70% conversion to allyl di-iso-propylcarbamate was achieved.

Into the mixture was added a second and final portion of allylchloroformate (1.75 mL, 16.5 mmol) and the resulting reaction mixturewas heated and stirred at 110° C. for an additional 24 hours. Themixture was concentrated under reduced pressure. The resulting oil wasanalyzed by ¹H NMR; greater than 95% conversion to allyldi-iso-propylcarbamate was achieved.

Example 14 Decarboxylative Allylation of Allyl Di-Iso-Propylcarbamate

Into a round bottom flask equipped with a stir bar was charged allyldi-iso-propylcarbamate (500 mg, 2.70 mmol) and dichloromethane (2.5 mL).The mixture was allowed to stir at a temperature of about 20° C. for 5minutes. To the mixture was addedtetrakis(triphenylphosphine)palladium[0] (62 mg, 0.054 mmol). Theresulting reaction mixture was allowed to stir at a temperature of about20° C. for 16 hours. The mixture was filtered through a pad of CELITEand the filtrate was concentrated under reduced pressure. The resultingoil was analyzed by HPLC and ¹H NMR; the results demonstrated thatgreater than 95% conversion to N,N-di-iso-propylallylamine was achieved.

Example 15 Alkylation of Noroxymorphone with Allyl Chloroformate

Into a round bottom flask equipped with a stir bar was chargednoroxymorphone (0.99 g, 3.45 mmol), acetone (5.0 mL), and allylchloroformate (0.35 mL, 3.29 mmol). The mixture was stirred at atemperature of about 20° C. To the stirred mixture was addedtriethylamine (0.05 mL, 0.36 mmol) and the resulting reaction mixturewas allowed to stir at a temperature of about 20° C. for 16 hours. Themixture was acidified to a pH of 1.0 with 0.75N aqueous hydrochloricacid (100 mL). The aqueous layer was extracted twice withdichloromethane (100 mL for each extraction). The organic portions werecombined and concentrated under reduced pressure. The resulting oil wasanalyzed by ¹H NMR; the NMR spectrum was consistent with the17-allyloxycarbonyl noroxymorphone product.

Example 16 Alkylation of Noroxymorphone with 3-ChloropropylChloroformate

Into a round bottom flask equipped with a stir bar was chargednoroxymorphone (1.00 g, 3.48 mmol), dichloromethane (5.0 mL), and3-chloropropyl chloroformate (0.40 mL, 3.32 mmol). The mixture wasstirred at a temperature of about 20° C. To the stirred mixture wasadded triethylamine (0.40 mL, 2.87 mmol) and the mixture was allowed tostir for 2 hours. To the mixture was added potassium carbonate (1.00 g,7.24 mmol) and ethanol (15 mL). The resulting reaction mixture washeated to 60° C. and stirred at that temperature for 16 hours. To themixture was added water (15 mL) and the mixture was cooled to atemperature of about 20° C. The mixture was acidified to a pH of 1.0with 0.75N aqueous hydrochloric acid (100 mL). The aqueous layer wasextracted twice with dichloromethane (20 mL for each extraction). Theorganic portions were combined and concentrated under reduced pressure.The resulting oil was analyzed by ¹H NMR; the NMR spectrum wasconsistent with the 3-chloropropyl noroxymorphone-17-carboxylateproduct.

Example 17 N-Demethylation of Oxymorphone with 3-ChloropropylChloroformate

Into a round bottom flask equipped with a stir bar and reflux condenserwas charged oxymorphone (10.02 g, 33.3 mmol), sodium bicarbonate (6.96g, 82.9 mmol), and tert-amyl alcohol (75 mL). The mixture was allowed tostir at a temperature of about 20° C. for 5 minutes. Into the mixturewas added 3-chloropropyl chloroformate (12.0 mL, 99.5 mmol) drop-wiseover 5 minutes. The resulting reaction mixture was heated to 80° C. andallowed to stir at that temperature for 16 hours. The mixture was cooledto a temperature of about 20° C. and treated with 1N aqueoushydrochloric acid (125 mL). The mixture was stirred at a temperature ofabout 20° C. for 15 minutes. The stirring was stopped and the organicand aqueous layers were allowed to separate. The organic layer wasconcentrated under reduced pressure. The resulting oil was analyzed byHPLC and ¹H NMR; the results were consistent with a 95:5 product ratioof 3-chloropropyl noroxymorphone-3,17-di-carboxylate:3-chloropropylnoroxymorphone-3,14,17-tri-carboxylate.

Example 18 Alternate Procedure for N-Demethylation of Oxycodone

Into a round bottom flask equipped with a distillation head, refluxcondenser, and stir bar was charged oxycodone (6.11 g, 19.37 mmol) andtoluene (50 mL). The mixture was stirred and heated to reflux under anatmosphere of nitrogen for 1.5 hours. The mixture was cooled to 84° C.and sodium bicarbonate (3.27 g, 38.92 mmol) was charged to the mixture.Into the mixture was added a first portion of allyl chloroformate (1.00mL, 9.44 mmol). The resulting reaction mixture was allowed to stir at84° C. until the conversion to the 17-allyloxycarbonyl-products did notincrease by HPLC analysis, approximately 16 hours.

Into the mixture was added a second portion of allyl chloroformate (1.00mL, 9.44 mmol). The resulting reaction mixture was allowed to stir at84° C. until the conversion to the 17-allyloxycarbonyl-products did notincrease by HPLC analysis, approximately 16 hours.

Into the mixture was added a third portion of allyl chloroformate (1.00mL, 9.44 mmol). The resulting reaction mixture was allowed to stir at84° C. until the conversion to the 17-allyloxycarbonyl-products did notincrease by HPLC analysis, approximately 16 hours.

Into the mixture was added a fourth and final portion of allylchloroformate (1.00 mL, 9.44 mmol). The resulting reaction mixture wasallowed to stir at 84° C. until the conversion to the17-allyloxycarbonyl-products did not increase by HPLC analysis,approximately 16 hours. The mixture was cooled to a temperature of about20° C. and washed twice with water (100 mL for each wash). HPLC analysisof the product demonstrated that a three component mixture ofoxycodone:17-allyloxycarbonyl-noroxycodone:14,17-di-allyloxycarbonyl-noroxycodonewas prepared, with an HPLC area % ratio of 19.3:28.8:51.9 (80.7%conversion to products comprising 17-allyloxycarbonyl).

All publications, patents, patent applications, and other documentscited in this application are hereby incorporated by reference in theirentireties for all purposes to the same extent as if each individualpublication, patent, patent application, or other document wereindividually indicated to be incorporated by reference for all purposes.

While various specific embodiments have been illustrated and described,it will be appreciated that various changes can be made withoutdeparting from the spirit and scope of the invention(s).

What is claimed is:
 1. A method for making a compound of Formula (1)

comprising contacting a compound of Formula (2)

with a compound of Formula (23)

and a base in a solvent to provide a compound of Formula (24)

and contacting the compound of Formula (24) with a transition metal catalyst to provide the compound of Formula (1); wherein: R¹, R², and R³ are each independently selected from —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups, or R¹ and R² are taken together with the nitrogen atom to which they are bound to form a heterocyclic or heteroaryl ring of Formula (5)

n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11; the heterocyclic or heteroaryl ring of Formula (5) is a monocyclic ring that is saturated, unsaturated non-heteroaryl, or heteroaryl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups, or is a subunit of a polycyclic ring system comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic, heterocyclic, aryl, or heteroaryl rings, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R⁵² groups; X is selected from —Cl, —Br, and —I; R⁴ is selected from the group consisting of —H, —(C₁-C₆) alkyl, phenyl, allyl, -2-butenyl, -3-butenyl, -4-pentenyl, -2-propynyl, -2-butynyl, -3-butynyl, -2-pentynyl,

R⁵, R⁶, and R⁷ are each independently selected from —H, —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups; each R⁸ is independently selected from —OR⁵¹, —F, —Br, —I, phenyl, and —(C₁-C₆) alkyl; each R⁵¹ is independently selected from —(C₁-C₆) alkyl and an oxygen protecting group; each R⁵² is independently selected from ═O, ═CH₂, —OR⁵³, —O(C₁-C₆) alkyl, —C(═O)(C₁-C₆) alkyl, and —(C₁-C₆) alkyl, each alkyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected —OR⁵³ groups; each R⁵³ is independently selected from —H and an oxygen protecting group; and V is a leaving group.
 2. The method of claim 1, wherein the leaving group is selected from —Cl, —Br, —I, —OS(O)₂C₄F₉, —OS(O)₂CF₃, —OS(O)₂F, -para-toluene sulfonate, —OS(O)₂CH₃, and —B(O(C₁-C₄) alkyl)₂.
 3. The method of claim 2, wherein R₃ is methyl.
 4. The method of claim 1, wherein R₃ is methyl.
 5. The method of claim 1, wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Pd[0], Pd[II], and combinations thereof.
 6. The method of claim 1, wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Pd[0], Pd[II], Ni[0], Ni[II], Mo[0], Ru[II], Rh[I], and combinations of two or more thereof.
 7. The method of claim 6, wherein the transition metal catalyst is selected from the group consisting of Pd(PPh₃)₄, Pd(Ph₂P(CH₂)₄PPh₂)₂, Ni(PPh₃)₄, Ni(Ph₂P(CH₂)₄PPh₂)₂, ((pentamethylcyclopentadienyl)RuCl)₄, [Pd(DBA)₂]/PPh₃, [Pd(OAc)₂]/PPh₃, [Ni(COD)₂]/PPh₃, NiCl₂/PPh₃, Ni[P(OEt)₃]₄, [Mo(CO)₆-DPPE], RhH(PPh₃)₄—P(n-Bu)₃, and combinations of two or more thereof.
 8. The method of claim 7, wherein R₃ is methyl.
 9. The method of claim 5, wherein R₃ is methyl.
 10. The method of claim 6, wherein R₃ is methyl.
 11. The method of claim 2, wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Pd[0], Pd[II], and combinations thereof.
 12. The method of claim 2, wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Pd[0], Pd[H], Ni[0], N[II], Ru[II], and combinations of two or more thereof.
 13. The method of claim 12, wherein the transition metal catalyst is selected from the group consisting of Pd(PPh₃)₄, Pd(Ph₂P(CH₂)₄PPh₂)₂, Ni(PPh₃)₄, Ni(Ph₂P(CH₂)₄PPh₂)₂, ((pentamethylcyclopentadienyl)RuCl)₄, [Pd(DBA)₂]/PPh₃, [Pd(OAc)₂]/PPh₃, [Ni(COD)₂]/PPh₃, NiCl₂/PPh₃, Ni[P(OEt)₃]₄, and combinations of two or more thereof.
 14. The method of claim 13, wherein R₃ is methyl.
 15. The method of claim 11, wherein R₃ is methyl.
 16. The method of claim 12, wherein R₃ is methyl.
 17. The method of claim 1, wherein: the oxygen protecting group is selected from the group consisting of allyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, —C(O)O—CH₂—CH═CH₂, tert-butyl-diphenylsilyl, [bis-(4-methoxyphenyl)phenylmethyl)], triphenylmethyl, —C(O)(C₁-C₄) alkyl, —C(O)OR¹⁸, and —(C₁-C₆) alkyl, each alkyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R²¹ groups; each R¹⁸ is independently selected from —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R²¹ groups; and each R²¹ is independently selected from —Cl, —Br, —I, —NH₂, —CN, and phenyl.
 18. The method of claim 17, wherein the oxygen protecting group is allyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, or —C(O)O—CH₂—CH═CH₂.
 19. The method of claim 1, wherein the solvent is selected from the group consisting of chloroform, dichloromethane, 1,2-dichloroethane, toluene, tetrahydrofuran, ethyl acetate, acetone, tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl-pentanol, 2-methyl-2-hexanol, acetonitrile, benzene, carbon tetrachloride, chlorobenzene, 1,2-dichlorobenzene, N,N-dimethylformamide, trifluorotoluene, 1,4-dioxane, 1,2-dimethoxyethane, xylene, and combinations of two or more thereof.
 20. The method of claim 19, wherein the solvent comprises tert-amyl alcohol, dichloromethane, or combinations thereof.
 21. The method of claim 1, wherein the base is selected from the group consisting of NaBO₃, Na₂HPO₄, Na₃PO₄, K₂HPO₄, K₃PO₄, NaHCO₃, KHCO₃, NaOH, KOH, Na₂CO₃, K₂CO₃, Cs₂CO₃, pyridine, triethylamine, di-iso-propylethylamine, N-methylmorpholine, N,N-dimethylaminopyridine, N-(2-acetamido)-2-aminoethane sulfonic acid, N-(2-acetamido)-iminodiacetic acid, N,N-bis(2-hydroxyethyl)glycine, 3-(cyclohexylamino)-1-propanesulfonic acid, 2-(cyclohexylamino) ethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, 2-(4-morpholinyl) ethanesulfonic acid, 4-morpholinepropanesulfonic acid, 1,4-piperazinediethanesulfonic acid, [(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid, 2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid, and combinations of two or more thereof.
 22. The method of claim 21, wherein the base is selected from the group consisting of K₃PO₄, NaHCO₃, KHCO₃, Na₂CO₃, K₂CO₃, Cs₂CO₃, triethylamine, di-iso-propylethylamine, and combinations of two or more thereof.
 23. The method of claim 21, wherein the base is selected from the group consisting of NaHCO₃, KHCO₃, Na₂CO₃, K₂CO₃, Cs₂CO₃, triethylamine, di-iso-propylethylamine, and combinations of two or more thereof.
 24. The method of claim 1, wherein: R⁴ is selected from hydrogen and unsubstituted —(C₁-C₆) alkyl; R⁵ is selected from hydrogen and unsubstituted —(C₁-C₆) alkyl; and R⁶ and R⁷ are each hydrogen.
 25. The method of claim 24, wherein: the compound of Formula (1) is a compound of Formula (200)

the compound of Formula (2) is a compound of Formula (45)

the compound of Formula (24) is a compound of Formula (211)

R⁵ is selected from —H, —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, wherein said alkyl, alkenyl, or alkynyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R⁸ groups; R⁶ and R⁷ are each hydrogen; R¹⁴ and R¹⁶ are each independently selected from —OH, —H, and —OR¹⁷; R¹⁵ is selected from —OH, —H, —OR¹⁷, ═O, and ═CH₂; and R¹⁷ is an oxygen protecting group.
 26. The method of claim 25, wherein: the oxygen protecting group is selected from the group consisting of allyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, —C(O)O—CH₂—CH═CH₂, tert-butyl-diphenylsilyl, [bis-(4-methoxyphenyl)phenylmethyl)], triphenylmethyl, —C(O)(C₁-C₄) alkyl, —C(O)OR¹⁸, and —(C₁-C₆) alkyl, each alkyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R²¹ groups; each R¹⁸ is independently selected from —(C₁-C₆) alkyl, —(C₂-C₆) alkenyl, and —(C₂-C₆) alkynyl, each alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R²¹ groups; and each R²¹ is independently selected from —Cl, —Br, —I, —NH₂, —CN, and phenyl.
 27. The method of claim 26, wherein the oxygen protecting group is allyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, or —C(O)O—CH₂—CH═CH₂.
 28. The method of claim 25, wherein: R¹⁴ and R¹⁶ are each —OH; and R¹⁵ is ═O. 